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UniProtKB/Swiss-Prot Q8WXG6: Variant p.Leu1040Arg

MAP kinase-activating death domain protein
Gene: MADD
Variant information

Variant position:  1040
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  LP/P [Disclaimer]
The variants are classified into three categories: LP/P, LB/B and US.
  • LP/P: likely pathogenic or pathogenic.
  • LB/B: likely benign or benign.
  • US: uncertain significance

Residue change:  From Leucine (L) to Arginine (R) at position 1040 (L1040R, p.Leu1040Arg).
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 medium size and hydrophobic (L) to large size and basic (R)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -2
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

Variant description:  In DEEAH; impaired TNFA-induced activation of the MAP kinases ERK1/2; enhanced susceptibility to TNFA-induced apoptosis; decreased EGF internalization.
Any additional useful information about the variant.



Sequence information

Variant position:  1040
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  1647
The length of the canonical sequence.

Location on the sequence:   LSLEQSYAHAGLGGMASIFG  L LEIAQTHYYSKEPDKRKRSP
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                         LSLEQSYAHAGLGGMASIFGLLEIAQTHYYSKE----PDKRKRSP

Mouse                         LSLEQSYAHAGLGGMASIFGLLEIAQTHYYSKE----PDKR

Rat                           LSLEQSYAHAGLGGMASIFGLLEIAQTHYYSKE----PDKR

Caenorhabditis elegans        EGIEVSFNTPGCCGFASVFHVLEIAHTHYWAMGGGEVITPS

Drosophila                    GGLDVTFANFGLGGMASVFQLMEVAHTHYWSKEINEGSDMS

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 1 – 1647 MAP kinase-activating death domain protein
Modified residue 1059 – 1059 Phosphoserine


Literature citations

Expanding the genetic heterogeneity of intellectual disability.
Anazi S.; Maddirevula S.; Salpietro V.; Asi Y.T.; Alsahli S.; Alhashem A.; Shamseldin H.E.; AlZahrani F.; Patel N.; Ibrahim N.; Abdulwahab F.M.; Hashem M.; Alhashmi N.; Al Murshedi F.; Al Kindy A.; Alshaer A.; Rumayyan A.; Al Tala S.; Kurdi W.; Alsaman A.; Alasmari A.; Banu S.; Sultan T.; Saleh M.M.; Alkuraya H.; Salih M.A.; Aldhalaan H.; Ben-Omran T.; Al Musafri F.; Ali R.; Suleiman J.; Tabarki B.; El-Hattab A.W.; Bupp C.; Alfadhel M.; Al Tassan N.; Monies D.; Arold S.T.; Abouelhoda M.; Lashley T.; Houlden H.; Faqeih E.; Alkuraya F.S.;
Hum. Genet. 136:1419-1429(2017)
Cited for: INVOLVEMENT IN NEDDISH; VARIANTS NEDDISH HIS-198 AND ARG-327--1647-SER DEL; VARIANT ARG-1040;

Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder.
Schneeberger P.E.; Kortuem F.; Korenke G.C.; Alawi M.; Santer R.; Woidy M.; Buhas D.; Fox S.; Juusola J.; Alfadhel M.; Webb B.D.; Coci E.G.; Abou Jamra R.; Siekmeyer M.; Biskup S.; Heller C.; Maier E.M.; Javaher-Haghighi P.; Bedeschi M.F.; Ajmone P.F.; Iascone M.; Peeters H.; Ballon K.; Jaeken J.; Rodriguez Alonso A.; Palomares-Bralo M.; Santos-Simarro F.; Meuwissen M.E.C.; Beysen D.; Kooy R.F.; Houlden H.; Murphy D.; Doosti M.; Karimiani E.G.; Mojarrad M.; Maroofian R.; Noskova L.; Kmoch S.; Honzik T.; Cope H.; Sanchez-Valle A.; Gelb B.D.; Kurth I.; Hempel M.; Kutsche K.;
Brain 143:2437-2453(2020)
Cited for: INVOLVEMENT IN DEEAH; VARIANTS DEEAH ARG-216--1647-SER DEL; PHE-257; VAL-305; ARG-327--1647-SER DEL; LEU-372; ARG-1040 AND TRP-1431--1647-SER DEL; VARIANTS NEDDISH PRO-346; LEU-354; PRO-945; SER-1213--1647-SER DEL; SER-1283; ARG-1318 AND ARG-1532--1647-SER DEL; CHARACTERIZATION OF VARIANTS DEEAH VAL-305; ARG-1040; FUNCTION;

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.