Is ABCB6 p.Val2Met (c.4G>A) pathogenic?

ABCB6 p.Val2Met (c.4G>A) is classified Uncertain significance in ABCB6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-12). AlphaMissense: likely benign (0.1907); Ultra-rare (popmax 0.037%, mid).

How common is ABCB6 p.Val2Met (c.4G>A) in the general population?

ABCB6 p.Val2Met (c.4G>A) is ultra-rare (popmax 0.037%, mid) (gnomAD).

What do computational predictors say about ABCB6 p.Val2Met (c.4G>A)?

AlphaMissense predicts likely benign (score 0.1907) — an in-silico prediction, not a clinical call.

ABCB6 p.Val2Met

c.4G>A · VCV4540808

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1907 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.037%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1907	likely benign
REVEL	0.272	benign-leaning
SaProt	LLR -8.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,732 bp · p 0.15 · regional, not allelic
Overall
CADD	23.3	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 0.037% Middle Eastern · 2/5,404 alleles

Filtering AF 0.0247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0212%

Overall 0.00212% 33/1,554,534 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.037%	2,702
African / African-American	0.0354%	2,825
Remaining individualsnot grpmax-eligible	0.0067%	14,935
South Asian	0.00119%	83,902

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.Val2Met
Coding: c.4G>A
MANE Select: NM_005689
Type: single nucleotide variant
Location: chr2:219218670 (GRCh38)
Gene constraint: LOEUF 0.984 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.17 · 16 PDB
Residue 2: the 'required for atpase activity' region; the 'required for the lysosomal targeting' region

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

Similar variants

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
ABCB6 p.Arg685His 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-val2met (accessed [today's date]).

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