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UniProtKB/Swiss-Prot P17405: Variant p.Arg602His

Sphingomyelin phosphodiesterase
Gene: SMPD1
Variant information

Variant position:  602
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Disease [Disclaimer]
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Arginine (R) to Histidine (H) at position 602 (R602H, p.Arg602His).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Change from large size and basic (R) to medium size and polar (H)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  0
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Involvement in disease:  Niemann-Pick disease A (NPDA) [MIM:257200]: An early-onset lysosomal storage disorder caused by failure to hydrolyze sphingomyelin to ceramide. It results in the accumulation of sphingomyelin and other metabolically related lipids in reticuloendothelial and other cell types throughout the body, leading to cell death. Niemann-Pick disease type A is a primarily neurodegenerative disorder characterized by onset within the first year of life, mental retardation, digestive disorders, failure to thrive, major hepatosplenomegaly, and severe neurologic symptoms. The severe neurological disorders and pulmonary infections lead to an early death, often around the age of four. Clinical features are variable. A phenotypic continuum exists between type A (basic neurovisceral) and type B (purely visceral) forms of Niemann-Pick disease, and the intermediate types encompass a cluster of variants combining clinical features of both types A and B. {ECO:0000269|PubMed:12556236, ECO:0000269|PubMed:1391960, ECO:0000269|PubMed:15221801, ECO:0000269|PubMed:15877209, ECO:0000269|PubMed:1618760, ECO:0000269|PubMed:1718266, ECO:0000269|PubMed:18815062, ECO:0000269|PubMed:19405096, ECO:0000269|PubMed:2023926, ECO:0000269|PubMed:20386867, ECO:0000269|PubMed:22818240, ECO:0000269|PubMed:23252888, ECO:0000269|PubMed:23430884, ECO:0000269|PubMed:26499107, ECO:0000269|PubMed:27338287, ECO:0000269|PubMed:8680412, ECO:0000269|PubMed:8693491, ECO:0000269|PubMed:9266408}. Note=The disease is caused by mutations affecting the gene represented in this entry.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Involvement in disease:  Niemann-Pick disease B (NPDB) [MIM:607616]: A late-onset lysosomal storage disorder caused by failure to hydrolyze sphingomyelin to ceramide. It results in the accumulation of sphingomyelin and other metabolically related lipids in reticuloendothelial and other cell types throughout the body, leading to cell death. Clinical signs involve only visceral organs. The most constant sign is hepatosplenomegaly which can be associated with pulmonary symptoms. Patients remain free of neurologic manifestations. However, a phenotypic continuum exists between type A (basic neurovisceral) and type B (purely visceral) forms of Niemann-Pick disease, and the intermediate types encompass a cluster of variants combining clinical features of both types A and B. In Niemann-Pick disease type B, onset of the first symptoms occurs in early childhood and patients can survive into adulthood. {ECO:0000269|PubMed:12369017, ECO:0000269|PubMed:12556236, ECO:0000269|PubMed:1301192, ECO:0000269|PubMed:15241805, ECO:0000269|PubMed:16010684, ECO:0000269|PubMed:1618760, ECO:0000269|PubMed:16472269, ECO:0000269|PubMed:18815062, ECO:0000269|PubMed:1885770, ECO:0000269|PubMed:19050888, ECO:0000269|PubMed:19405096, ECO:0000269|PubMed:20386867, ECO:0000269|PubMed:21621718, ECO:0000269|PubMed:22613662, ECO:0000269|PubMed:22818240, ECO:0000269|PubMed:23252888, ECO:0000269|PubMed:23430512, ECO:0000269|PubMed:25920558, ECO:0000269|PubMed:26084044, ECO:0000269|PubMed:26499107, ECO:0000269|PubMed:27338287, ECO:0000269|PubMed:27659707, ECO:0000269|PubMed:8051942, ECO:0000269|PubMed:8664904}. Note=The disease is caused by mutations affecting the gene represented in this entry.
The name and a short description of the disease associated with the variant. For more information about the disease, the user can refer to OMIM, following the link provided after the disease acronym.

Variant description:  In NPDB and NPDA; expresses protein level comparable to wild-type SMPD1 expressing cells; retains about 10% residual enzyme activity.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.



Sequence information

Variant position:  602
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  631
The length of the canonical sequence.

Location on the sequence:   PSEPCGTPCRLATLCAQLSA  R ADSPALCRHLMPDGSLPEAQ
The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Residue conservation: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         PSEPCGTPCRLATLCAQLSARADSPALCRHLMPDGSLPEAQ

Mouse                         PSEPCGTPCRLATLCAQLSARADSPALCRHLMPNGSLPDAN

Bovine                        PSEPCGTPCRLATLCAQLSARSDSPALCRHLVPDASLPDVQ

Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

TypePositionsDescription
Chain 47 – 631 Sphingomyelin phosphodiesterase
Disulfide bond 596 – 609
Beta strand 602 – 604


Literature citations

The demographics and distribution of type B Niemann-Pick disease: novel mutations lead to new genotype/phenotype correlations.
Simonaro C.M.; Desnick R.J.; McGovern M.M.; Wasserstein M.P.; Schuchman E.H.;
Am. J. Hum. Genet. 71:1413-1419(2002)
Cited for: VARIANTS NPDB VAL-51; TRP-94; PRO-139; ARG-159; PRO-198; CYS-202; MET-227; CYS-230; ASP-234; SER-247; ARG-250; HIS-291; ALA-325; ARG-332; ASP-359; HIS-378; LEU-378; PRO-381; VAL-415; TYR-423; ARG-433; PRO-434; CYS-437; VAL-454; ASP-458; TRP-476; LEU-477; LEU-482; ASN-490; SER-496; CYS-498; GLN-516; VAL-517; ARG-535; PRO-551; ASN-578; HIS-602 AND PRO-602; VARIANT VAL-487;

Functional in vitro characterization of 14 SMPD1 mutations identified in Italian patients affected by Niemann Pick type B disease.
Dardis A.; Zampieri S.; Filocamo M.; Burlina A.; Bembi B.; Pittis M.G.;
Hum. Mutat. 26:164-164(2005)
Cited for: VARIANTS NPDB ALA-132 AND TYR-565; CHARACTERIZATION OF VARIANTS NPDB PRO-105; ALA-132; PRO-227; CYS-246; THR-283; TYR-565; HIS-602 AND PRO-602;

Spectrum of SMPD1 mutations in Asian-Indian patients with acid sphingomyelinase (ASM)-deficient Niemann-Pick disease.
Ranganath P.; Matta D.; Bhavani G.S.; Wangnekar S.; Jain J.M.; Verma I.C.; Kabra M.; Puri R.D.; Danda S.; Gupta N.; Girisha K.M.; Sankar V.H.; Patil S.J.; Ramadevi A.R.; Bhat M.; Gowrishankar K.; Mandal K.; Aggarwal S.; Tamhankar P.M.; Tilak P.; Phadke S.R.; Dalal A.;
Am. J. Med. Genet. A 170:2719-2730(2016)
Cited for: VARIANTS ALA-36; PHE-510 AND GLY-605; VARIANTS NPDA ARG-216; CYS-230; SER-255; ARG-319; PRO-324; ARG-343; ARG-363; HIS-391; ARG-393; SER-426; ILE-494; HIS-498; ARG-535 AND HIS-602; VARIANTS NPDB PRO-105; PHE-282; ASP-320; CYS-369; SER-465; LEU-520 AND LYS-549;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.