Is ABCB4 p.Ile763Met (c.2289T>G) pathogenic?

ABCB4 p.Ile763Met (c.2289T>G) is classified Uncertain significance in ABCB4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-20). AlphaMissense: likely benign (0.0784); Ultra-rare (popmax 0.025%, amr).

How common is ABCB4 p.Ile763Met (c.2289T>G) in the general population?

ABCB4 p.Ile763Met (c.2289T>G) is ultra-rare (popmax 0.025%, amr) (gnomAD).

What do computational predictors say about ABCB4 p.Ile763Met (c.2289T>G)?

AlphaMissense predicts likely benign (score 0.0784) — an in-silico prediction, not a clinical call.

ABCB4 p.Ile763Met

c.2289T>G · rs777880618 · VCV593288

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0784 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0784	likely benign
REVEL	0.398	indeterminate
SaProt	LLR -9.72	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -0.64, phastCons 0.037
Regional constraint	o/e 0.97	unconstrained · MANE · 14 kb · p 0.53 · regional, not allelic
Overall
CADD	17.18	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 0.025% Admixed American · 15/60,000 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.00093% 15/1,612,584 alleles · ultra-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: ABCB4
Protein: p.Ile763Met
Coding: c.2289T>G
MANE Select: NM_000443
dbSNP: rs777880618
Type: single nucleotide variant
Location: chr7:87422148 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 763: an α-helix; the abc transmembrane type-1 2 domain

Full ABCB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCB4 p.Ile763Phe Uncertain significance ★★ ⚠ same residue
ABCB4 p.Ile763Thr Uncertain significance ★★ ⚠ same residue
ABCB4 c.1006-2A>C Pathogenic ★★ same type
ABCB4 c.1356+2T>C Pathogenic/Likely pathogenic ★★ same type
ABCB4 c.1560+1G>A Likely pathogenic ★★ same type
ABCB4 c.2064+3A>T Likely pathogenic ★★ same type
ABCB4 c.2211+1G>A Pathogenic/Likely pathogenic ★★ same type
ABCB4 c.2682+1G>A Pathogenic/Likely pathogenic ★★ 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/abcb4-p-ile763met (accessed [today's date]).

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