Is ABCB11 p.Ser699Pro (c.2095T>C) pathogenic?

ABCB11 p.Ser699Pro (c.2095T>C) is classified Conflicting classifications of pathogenicity in ABCB11 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-04-14). AlphaMissense: likely benign (0.2998); Very rare (popmax 0.000347%, nfe); Associated with familial intrahepatic cholestasis.

What condition is associated with ABCB11 p.Ser699Pro (c.2095T>C)?

ABCB11 p.Ser699Pro (c.2095T>C) is associated with familial intrahepatic cholestasis, progressive familial intrahepatic cholestasis type 2, benign recurrent intrahepatic cholestasis type 2 (ClinVar).

How common is ABCB11 p.Ser699Pro (c.2095T>C) in the general population?

ABCB11 p.Ser699Pro (c.2095T>C) is very rare (popmax 0.000347%, nfe) (gnomAD).

What do computational predictors say about ABCB11 p.Ser699Pro (c.2095T>C)?

AlphaMissense predicts likely benign (score 0.2998) — an in-silico prediction, not a clinical call.

ABCB11 p.Ser699Pro

c.2095T>C · rs867525294 · VCV595385

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.2998 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000347%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial intrahepatic cholestasis

Computational evidence

Protein change
AlphaMissense	0.2998	likely benign
REVEL	0.555	indeterminate
SaProt	LLR -9.96	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Overall
CADD	25.4	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

Grpmax group 0.000347% European (non-Finnish) · 4/1,154,140 alleles

Filtering AF 8.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.5e-05%

Overall 0.000283% 4/1,415,096 alleles · very rare

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.Ser699Pro
Coding: c.2095T>C
MANE Select: NM_003742
dbSNP: rs867525294
Type: single nucleotide variant
Location: chr2:168964289 (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 699: an α-helix

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

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

Similar variants

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
ABCB11 c.150+2T>C Pathogenic/Likely pathogenic ★★ same condition
ABCB11 c.150+3A>C 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-ser699pro (accessed [today's date]).

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