Is ABCB4 p.Val683Met (c.2047G>A) pathogenic?

ABCB4 p.Val683Met (c.2047G>A) is classified Conflicting classifications of pathogenicity in ABCB4 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-29). AlphaMissense: likely benign (0.076); Rare (popmax 0.148%, amr); Associated with cholestasis, intrahepatic, of pregnancy, 3.

What condition is associated with ABCB4 p.Val683Met (c.2047G>A)?

ABCB4 p.Val683Met (c.2047G>A) is associated with cholestasis, intrahepatic, of pregnancy, 3, progressive familial intrahepatic cholestasis type 3 (ClinVar).

How common is ABCB4 p.Val683Met (c.2047G>A) in the general population?

ABCB4 p.Val683Met (c.2047G>A) is rare (popmax 0.148%, amr) (gnomAD).

How is Intrahepatic cholestasis of pregnancy inherited?

Typically Multigenic/multifactorial, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ABCB4 p.Val683Met (c.2047G>A)?

AlphaMissense predicts likely benign (score 0.076) — an in-silico prediction, not a clinical call.

ABCB4 p.Val683Met

c.2047G>A · rs776616540 · VCV360796

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.076 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.148%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cholestasis, intrahepatic, of pregnancy, 3

Computational evidence

Protein change
AlphaMissense	0.076	likely benign
REVEL	0.158	moderately benign-leaning
SaProt	LLR -7.00	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 1.3	GERP -1, phastCons 0.02
Regional constraint	o/e 0.97	unconstrained · MANE · 14 kb · p 0.53 · regional, not allelic
Overall
CADD	13.3	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 0.148% Admixed American · 89/59,994 alleles

Filtering AF 0.123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.114%

Overall 0.00589% 95/1,613,858 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.148%	674
African / African-American	0.00801%	12,486

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.Val683Met
Coding: c.2047G>A
MANE Select: NM_000443
dbSNP: rs776616540
Type: single nucleotide variant
Location: chr7:87426767 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB

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

Disease context

cholestasis, intrahepatic, of pregnancy, 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: progressive familial intrahepatic cholestasis type 3

For Intrahepatic cholestasis of pregnancy (Orphanet):

Inheritance: Multigenic/multifactorial, Not applicable
Onset: Adult

Similar variants

ABCB4 c.1560+1G>A Likely pathogenic ★★ same condition
ABCB4 c.2211+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.2682+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.3081+1G>C Pathogenic ★★ same condition
ABCB4 c.3486+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.834-1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCB4 p.Arg1046Ter Pathogenic/Likely pathogenic ★★ same condition
ABCB4 p.Arg144Ter Pathogenic ★★ 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/abcb4-p-val683met (accessed [today's date]).

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