Is ABCB6 p.Ala373Val (c.1118C>T) pathogenic?

ABCB6 p.Ala373Val (c.1118C>T) is classified Uncertain significance in ABCB6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-18). AlphaMissense: likely benign (0.0578); Ultra-rare (popmax 0.0179%, mid).

How common is ABCB6 p.Ala373Val (c.1118C>T) in the general population?

ABCB6 p.Ala373Val (c.1118C>T) is ultra-rare (popmax 0.0179%, mid) (gnomAD).

What do computational predictors say about ABCB6 p.Ala373Val (c.1118C>T)?

AlphaMissense predicts likely benign (score 0.0578) — an in-silico prediction, not a clinical call.

ABCB6 p.Ala373Val

c.1118C>T · VCV3704374

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0578 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0179%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0578	likely benign
REVEL	0.265	benign-leaning
SaProt	LLR -5.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.3	GERP 1.2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,732 bp · p 0.15 · regional, not allelic
Overall
CADD	15.23	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0179% Middle Eastern · 1/5,584 alleles

Filtering AF 0.00299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00203%

Overall 0.003% 48/1,601,772 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0179%	5,584
East Asian	0.00898%	11,140
South Asian	0.00443%	22,551
European (non-Finnish)	0.00315%	31,698
Admixed American	0.00168%	59,438
African / African-American	0.00134%	74,690

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.Ala373Val
Coding: c.1118C>T
MANE Select: NM_005689
Type: single nucleotide variant
Location: chr2:219216033 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.17 · 16 PDB
Residue 373: the abc transmembrane type-1 domain; an α-helix

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

Similar variants

ABCB6 p.Ala373= Likely benign ★★ same residue
ABCB6 p.Ala164Thr Uncertain significance ★★ ⚠ same type
ABCB6 p.Ala57Thr Uncertain significance ★★ ⚠ same type
ABCB6 p.Ala66Thr Uncertain significance ★★ ⚠ same type
ABCB6 p.Ala681Thr Uncertain significance ★★ ⚠ same type
ABCB6 p.Arg135Ser Uncertain significance ★★ ⚠ same type
ABCB6 p.Arg439Cys Uncertain significance ★★ ⚠ same type
ABCB6 p.Arg450Gln Uncertain significance ★★ ⚠ same type

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-ala373val (accessed [today's date]).

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