Is ABCB11 p.Phe774Ser (c.2321T>C) pathogenic?

ABCB11 p.Phe774Ser (c.2321T>C) is classified Uncertain significance in ABCB11 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-14). AlphaMissense: likely pathogenic (0.6128); Absent from gnomAD v4.1; Associated with familial intrahepatic cholestasis.

What condition is associated with ABCB11 p.Phe774Ser (c.2321T>C)?

ABCB11 p.Phe774Ser (c.2321T>C) is associated with familial intrahepatic cholestasis (ClinVar).

How common is ABCB11 p.Phe774Ser (c.2321T>C) in the general population?

ABCB11 p.Phe774Ser (c.2321T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ABCB11 p.Phe774Ser (c.2321T>C)?

AlphaMissense predicts likely pathogenic (score 0.6128) — an in-silico prediction, not a clinical call.

ABCB11 p.Phe774Ser

c.2321T>C · VCV4846000

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6128 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial intrahepatic cholestasis

Computational evidence

Protein change
AlphaMissense	0.6128	likely pathogenic
REVEL	0.516	indeterminate
SaProt	LLR -6.67	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 0.56, phastCons 1
Overall
CADD	23.4	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

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: ABCB11
Protein: p.Phe774Ser
Coding: c.2321T>C
MANE Select: NM_003742
Type: single nucleotide variant
Location: chr2:168957986 (GRCh38)
Gene constraint: LOEUF 0.739 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 83.23 · 9 PDB
Residue 774: an α-helix; the abc transmembrane type-1 2 domain

Full ABCB11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Similar variants

ABCB11 p.Phe774fs Pathogenic/Likely pathogenic ★★ same residue
ABCB11 c.1084-2A>G Pathogenic ★★ same condition
ABCB11 c.1197+1G>T Pathogenic/Likely pathogenic ★★ same condition
ABCB11 c.1198-1G>C Pathogenic/Likely pathogenic ★★ same condition
ABCB11 c.1435-2A>T Pathogenic/Likely pathogenic ★★ same condition
ABCB11 c.150+3A>C Pathogenic/Likely pathogenic ★★ same condition
ABCB11 c.1638+1G>C Likely pathogenic ★★ same condition
ABCB11 c.2012-2A>G 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/abcb11-p-phe774ser (accessed [today's date]).

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