Is ABCB4 p.Ser978Pro (c.2932T>C) pathogenic?

ABCB4 p.Ser978Pro (c.2932T>C) is classified Likely pathogenic in ABCB4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-04-14). AlphaMissense: likely pathogenic (0.9475); Very rare (popmax 0.000593%, nfe); Associated with ABCB4-Related Intrahepatic Cholestasis.

What condition is associated with ABCB4 p.Ser978Pro (c.2932T>C)?

ABCB4 p.Ser978Pro (c.2932T>C) is associated with ABCB4-Related Intrahepatic Cholestasis, gallbladder disease 1, progressive familial intrahepatic cholestasis type 3 (ClinVar).

How common is ABCB4 p.Ser978Pro (c.2932T>C) in the general population?

ABCB4 p.Ser978Pro (c.2932T>C) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about ABCB4 p.Ser978Pro (c.2932T>C)?

AlphaMissense predicts likely pathogenic (score 0.9475) — an in-silico prediction, not a clinical call.

ABCB4 p.Ser978Pro

c.2932T>C · rs1051861187 · VCV599183

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9475 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ABCB4-Related Intrahepatic Cholestasis

Computational evidence

Protein change
AlphaMissense	0.9475	likely pathogenic ✓ concordant with ClinVar
REVEL	0.899	moderately pathogenic-leaning
SaProt	LLR -13.90	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 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 14 kb · p 8.2e-06 · regional, not allelic
Overall
CADD	23.3	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 0.000593% European (non-Finnish) · 7/1,179,918 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,862 alleles · very rare exomes 6/1,461,634 · genomes 1/152,228 · joint denominator

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.Ser978Pro
Coding: c.2932T>C
MANE Select: NM_000443
dbSNP: rs1051861187
Type: single nucleotide variant
Location: chr7:87409385 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 978: a UniProt-annotated variant site (in pfic3; alters efflux activity for pc); an α-helix; the abc transmembrane type-1 2 domain

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

Disease context

ABCB4-Related Intrahepatic Cholestasis

Also linked: gallbladder disease 1 progressive familial intrahepatic cholestasis type 3 cholestasis, intrahepatic, of pregnancy, 3 progressive familial intrahepatic cholestasis familial intrahepatic cholestasis

Similar variants

ABCB4 c.1356+2T>C Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.1560+1G>A Likely pathogenic ★★ same condition
ABCB4 c.2064+3A>T 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.2783+1G>T Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.286+1G>A Pathogenic ★★ same condition
ABCB4 c.3081+1G>C 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-ser978pro (accessed [today's date]).

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