Is ABCB11 p.Ala693Pro (c.2077G>C) pathogenic?

ABCB11 p.Ala693Pro (c.2077G>C) is classified Conflicting classifications of pathogenicity in ABCB11 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-04-14). AlphaMissense: likely benign (0.275); Ultra-rare (popmax 0.0669%, eas); Associated with benign recurrent intrahepatic cholestasis type 2.

What condition is associated with ABCB11 p.Ala693Pro (c.2077G>C)?

ABCB11 p.Ala693Pro (c.2077G>C) is associated with benign recurrent intrahepatic cholestasis type 2, progressive familial intrahepatic cholestasis type 2, familial intrahepatic cholestasis (ClinVar).

How common is ABCB11 p.Ala693Pro (c.2077G>C) in the general population?

ABCB11 p.Ala693Pro (c.2077G>C) is ultra-rare (popmax 0.0669%, eas) (gnomAD).

How is Benign recurrent intrahepatic cholestasis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ABCB11 p.Ala693Pro (c.2077G>C)?

AlphaMissense predicts likely benign (score 0.275) — an in-silico prediction, not a clinical call.

ABCB11 p.Ala693Pro

c.2077G>C · rs748837264 · VCV2679692

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.275 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0669%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

benign recurrent intrahepatic cholestasis type 2

Computational evidence

Protein change
AlphaMissense	0.275	likely benign
REVEL	0.41	indeterminate
SaProt	LLR -6.28	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 2, phastCons 1
Overall
CADD	22.6	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 0.0669% East Asian · 28/41,882 alleles

Filtering AF 0.0474% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0409%

Overall 0.00186% 29/1,558,478 alleles · ultra-rare exomes 29/1,406,618 · genomes 0/151,860 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0669%	1,496
African / African-American	0.00136%	73,596

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: ABCB11
Protein: p.Ala693Pro
Coding: c.2077G>C
MANE Select: NM_003742
dbSNP: rs748837264
Type: single nucleotide variant
Location: chr2:168964307 (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 693: an α-helix

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

Disease context

benign recurrent intrahepatic cholestasis type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: progressive familial intrahepatic cholestasis type 2 familial intrahepatic cholestasis

For Benign recurrent intrahepatic cholestasis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages

Similar variants

ABCB11 p.Ala693Thr Uncertain significance ★★ ⚠ same residue
ABCB11 p.Ala693= Likely benign ★ 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.1198-2A>C Likely pathogenic ★★ same condition
ABCB11 c.1435-2A>T Pathogenic/Likely pathogenic ★★ same condition
ABCB11 c.150+1G>A Pathogenic/Likely 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-ala693pro (accessed [today's date]).

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