Is ABCB4 p.Ala248Pro (c.742G>C) pathogenic?

ABCB4 p.Ala248Pro (c.742G>C) is classified Uncertain significance in ABCB4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-26). AlphaMissense: likely pathogenic (0.9857); Absent from gnomAD v4.1; Associated with cholestasis, intrahepatic, of pregnancy, 3.

What condition is associated with ABCB4 p.Ala248Pro (c.742G>C)?

ABCB4 p.Ala248Pro (c.742G>C) is associated with cholestasis, intrahepatic, of pregnancy, 3 (ClinVar).

How common is ABCB4 p.Ala248Pro (c.742G>C) in the general population?

ABCB4 p.Ala248Pro (c.742G>C) is absent from gnomAD v4.1 (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.Ala248Pro (c.742G>C)?

AlphaMissense predicts likely pathogenic (score 0.9857) — an in-silico prediction, not a clinical call.

ABCB4 p.Ala248Pro

c.742G>C · rs2546854263 · VCV3065357

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9857 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cholestasis, intrahepatic, of pregnancy, 3

Computational evidence

Protein change
AlphaMissense	0.9857	likely pathogenic · top 4% in ABCB4
REVEL	0.82	moderately pathogenic-leaning
SaProt	LLR -14.78	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 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 31 kb · p 4.4e-11 · regional, not allelic
Overall
CADD	29.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ABCB4
Protein: p.Ala248Pro
Coding: c.742G>C
MANE Select: NM_000443
dbSNP: rs2546854263
Type: single nucleotide variant
Location: chr7:87450059 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 248: an α-helix; the abc transmembrane type-1 1 domain

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

For Intrahepatic cholestasis of pregnancy (Orphanet):

Inheritance: Multigenic/multifactorial, Not applicable
Onset: Adult

Similar variants

ABCB4 p.Ala248= Likely benign ★ same residue
ABCB4 c.2211+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.2682+1G>A Pathogenic/Likely 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
ABCB4 p.Arg159Ter 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-ala248pro (accessed [today's date]).

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