Is ABCB6 p.Glu433Ala (c.1298A>C) pathogenic?

ABCB6 p.Glu433Ala (c.1298A>C) is classified Uncertain significance in ABCB6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-13). AlphaMissense: likely pathogenic (0.6663); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with ABCB6 p.Glu433Ala (c.1298A>C)?

ABCB6 p.Glu433Ala (c.1298A>C) is associated with Inborn genetic diseases (ClinVar).

How common is ABCB6 p.Glu433Ala (c.1298A>C) in the general population?

ABCB6 p.Glu433Ala (c.1298A>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ABCB6 p.Glu433Ala (c.1298A>C)?

AlphaMissense predicts likely pathogenic (score 0.6663) — an in-silico prediction, not a clinical call.

ABCB6 p.Glu433Ala

c.1298A>C · rs1246658714 · VCV3123974

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6663 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6663	likely pathogenic
REVEL	0.825	moderately pathogenic-leaning
SaProt	LLR -12.11	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 7.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,732 bp · p 0.15 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,004 alleles

Overall 0.000657% 1/152,162 alleles · very rare

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.Glu433Ala
Coding: c.1298A>C
MANE Select: NM_005689
dbSNP: rs1246658714
Type: single nucleotide variant
Location: chr2:219214477 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.17 · 16 PDB
Residue 433: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ABCB6 p.Ala57Thr Uncertain significance ★★ ⚠ same condition
ABCB6 p.Ala66Thr Uncertain significance ★★ ⚠ same condition
ABCB6 p.Arg439Cys Uncertain significance ★★ ⚠ same condition
ABCB6 p.Arg450Gln Uncertain significance ★★ ⚠ same condition
ABCB6 p.Arg685His Uncertain significance ★★ ⚠ same condition
ABCB6 p.Arg688Gly Uncertain significance ★★ ⚠ same condition
ABCB6 p.Arg688His Uncertain significance ★★ ⚠ same condition
ABCB6 p.Asn545Ser Uncertain significance ★★ ⚠ 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-glu433ala (accessed [today's date]).

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