Is ABCB6 p.Val504Ala (c.1511T>C) pathogenic?

ABCB6 p.Val504Ala (c.1511T>C) is classified Conflicting classifications of pathogenicity in ABCB6 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-06-01). AlphaMissense: ambiguous (0.5084); Very rare (popmax 0.00439%, sas); Associated with microphthalmia, isolated, with coloboma 7.

What condition is associated with ABCB6 p.Val504Ala (c.1511T>C)?

ABCB6 p.Val504Ala (c.1511T>C) is associated with microphthalmia, isolated, with coloboma 7, familial pseudohyperkalemia, dyschromatosis universalis hereditaria 3 (ClinVar).

How common is ABCB6 p.Val504Ala (c.1511T>C) in the general population?

ABCB6 p.Val504Ala (c.1511T>C) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about ABCB6 p.Val504Ala (c.1511T>C)?

AlphaMissense predicts ambiguous (score 0.5084) — an in-silico prediction, not a clinical call.

ABCB6 p.Val504Ala

c.1511T>C · rs763768429 · VCV1283915

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5084 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

microphthalmia, isolated, with coloboma 7

Computational evidence

Protein change
AlphaMissense	0.5084	ambiguous
REVEL	0.706	pathogenic-leaning
SaProt	LLR -10.62	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,732 bp · p 0.15 · regional, not allelic
Overall
CADD	24.2	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 0.00439% South Asian · 4/91,092 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000682% 11/1,614,002 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,773
Finnishnot grpmax-eligible	0.00156%	63,968
European (non-Finnish)	0.000508%	196,672

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.Val504Ala
Coding: c.1511T>C
MANE Select: NM_005689
dbSNP: rs763768429
Type: single nucleotide variant
Location: chr2:219213893 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.17 · 16 PDB
Residue 504: the abc transmembrane type-1 domain; an α-helix

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

Disease context

microphthalmia, isolated, with coloboma 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial pseudohyperkalemia dyschromatosis universalis hereditaria 3

Similar variants

ABCB6 p.Val504= Likely benign ★ 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-val504ala (accessed [today's date]).

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