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UniProtKB/Swiss-Prot O14678: Variant p.Arg432Gln

Lysosomal cobalamin transporter ABCD4
Gene: ABCD4
Variant information

Variant position:  432
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 Arginine (R) to Glutamine (Q) at position 432 (R432Q, p.Arg432Gln).
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 (Q)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  1
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 MAHCJ; decreases interaction with LMBD1. Does not affect lysosomal subcellular location. Decreases ATPase activity.
Any additional useful information about the variant.



Sequence information

Variant position:  432
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  606
The length of the canonical sequence.

Location on the sequence:   SEGQSLLITGNTGTGKTSLL  R VLGGLWTSTRGSVQMLTDFG
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                         SEGQSLLITGNTGTGKTSLLRVLGGLWTSTRGSVQMLTDFG

Mouse                         CEGQSLLITGNTGTGKTSLLRVLGGLWEGMKGSVQMLADFG

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 – 606 Lysosomal cobalamin transporter ABCD4
Domain 389 – 603 ABC transporter
Mutagenesis 426 – 426 G -> A. Decreases interaction with LMBD1. Decreases colocalization with LMBD1. Decreases cobalamin transport activity.
Mutagenesis 427 – 427 K -> A. Loss of ATPase activity. Loss of cobalamin transport activity.
Mutagenesis 427 – 427 K -> L. Decreases interaction with LMBD1. Decreases colocalization with LMBD1. Decreases cobalamin transport activity. Reduces synthesis of adenosylcobalamin and methylcobalamin.


Literature citations

Clinical or ATPase domain mutations in ABCD4 disrupt the interaction between the vitamin B12-trafficking proteins ABCD4 and LMBD1.
Fettelschoss V.; Burda P.; Sagne C.; Coelho D.; De Laet C.; Lutz S.; Suormala T.; Fowler B.; Pietrancosta N.; Gasnier B.; Bornhauser B.; Froese D.S.; Baumgartner M.R.;
J. Biol. Chem. 292:11980-11991(2017)
Cited for: INVOLVEMENT IN MAHCJ; VARIANT MAHCJ GLN-432; CHARACTERIZATION OF VARIANTS MAHCJ LYS-141 AND GLN-432; SUBCELLULAR LOCATION; INTERACTION WITH LMBRD1; MUTAGENESIS OF GLY-426; LYS-427 AND ASP-548; FUNCTION; CATALYTIC ACTIVITY;

Cryo-EM structure of human lysosomal cobalamin exporter ABCD4.
Xu D.; Feng Z.; Hou W.T.; Jiang Y.L.; Wang L.; Sun L.; Zhou C.Z.; Chen Y.;
Cell Res. 29:1039-1041(2019)
Cited for: STRUCTURE BY ELECTRON MICROSCOPY (3.60 ANGSTROMS) OF 2-606; CHARACTERIZATION OF VARIANTS MAHCJ CYS-319 AND GLN-432; MUTAGENESIS OF GLU-549; FUNCTION; CATALYTIC ACTIVITY; BIOPHYSICOCHEMICAL PROPERTIES;

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.