Is ABCB6 p.Arg375Trp (c.1123C>T) pathogenic?

ABCB6 p.Arg375Trp (c.1123C>T) is classified Conflicting classifications of pathogenicity in ABCB6 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-07-10). AlphaMissense: likely pathogenic (0.8942); Very rare (popmax 0.00111%, sas); Associated with dyschromatosis universalis hereditaria 3.

What condition is associated with ABCB6 p.Arg375Trp (c.1123C>T)?

ABCB6 p.Arg375Trp (c.1123C>T) is associated with dyschromatosis universalis hereditaria 3, familial pseudohyperkalemia, microphthalmia, isolated, with coloboma 7 (ClinVar).

How common is ABCB6 p.Arg375Trp (c.1123C>T) in the general population?

ABCB6 p.Arg375Trp (c.1123C>T) is very rare (popmax 0.00111%, sas) (gnomAD).

How is Dyschromatosis universalis hereditaria inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ABCB6 p.Arg375Trp (c.1123C>T)?

AlphaMissense predicts likely pathogenic (score 0.8942) — an in-silico prediction, not a clinical call.

ABCB6 p.Arg375Trp

c.1123C>T · rs764893806 · VCV218180

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8942 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dyschromatosis universalis hereditaria 3

Computational evidence

Protein change
AlphaMissense	0.8942	likely pathogenic
REVEL	0.842	moderately pathogenic-leaning
SaProt	LLR -16.57	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,732 bp · p 0.15 · regional, not allelic
Overall
CADD	29.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00111% South Asian · 1/90,004 alleles

Overall 0.000138% 2/1,447,846 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00111%	90,004
European (non-Finnish)	8.54e-05%	1,171,580

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ABCB6
Protein: p.Arg375Trp
Coding: c.1123C>T
MANE Select: NM_005689
dbSNP: rs764893806
Type: single nucleotide variant
Location: chr2:219216028 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.17 · 16 PDB
Residue 375: the abc transmembrane type-1 domain; a UniProt-annotated variant site (in pshk2); an α-helix

Full ABCB6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

dyschromatosis universalis hereditaria 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial pseudohyperkalemia microphthalmia, isolated, with coloboma 7

For Dyschromatosis universalis hereditaria (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Childhood, Infancy

Similar variants

ABCB6 p.Arg375Gln Pathogenic same residue
ABCB6 p.Ala57Thr Uncertain significance ★★ ⚠ same condition
ABCB6 p.Arg723Gln Uncertain significance ★★ ⚠ same condition
ABCB6 p.Arg739Cys Uncertain significance ★★ ⚠ same condition
ABCB6 p.Glu220Val Uncertain significance ★★ ⚠ same condition
ABCB6 p.Gly317Trp Uncertain significance ★★ ⚠ same condition
ABCB6 p.Phe565Ser Uncertain significance ★★ ⚠ same condition
ABCB6 c.688-9C>T Benign/Likely benign ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/abcb6-p-arg375trp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown