Is ABCB11 p.Phe508Ser (c.1523T>C) pathogenic?

ABCB11 p.Phe508Ser (c.1523T>C) is classified Uncertain significance in ABCB11 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-09). AlphaMissense: likely pathogenic (0.9071); Absent from gnomAD v4.1; Associated with benign recurrent intrahepatic cholestasis type 2.

What condition is associated with ABCB11 p.Phe508Ser (c.1523T>C)?

ABCB11 p.Phe508Ser (c.1523T>C) is associated with benign recurrent intrahepatic cholestasis type 2 (ClinVar).

How common is ABCB11 p.Phe508Ser (c.1523T>C) in the general population?

ABCB11 p.Phe508Ser (c.1523T>C) is absent from gnomAD v4.1 (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.Phe508Ser (c.1523T>C)?

AlphaMissense predicts likely pathogenic (score 0.9071) — an in-silico prediction, not a clinical call.

ABCB11 p.Phe508Ser

c.1523T>C · rs1693598529 · VCV1707592

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9071 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

benign recurrent intrahepatic cholestasis type 2

Computational evidence

Protein change
AlphaMissense	0.9071	likely pathogenic · top 10% in ABCB11
REVEL	0.958	strongly pathogenic-leaning
SaProt	LLR -15.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.28	acceptor loss, 18 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Overall
CADD	32.0	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: ABCB11
Protein: p.Phe508Ser
Coding: c.1523T>C
MANE Select: NM_003742
dbSNP: rs1693598529
Type: single nucleotide variant
Location: chr2:168971962 (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 508: the abc transporter 1 domain

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

For Benign recurrent intrahepatic cholestasis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages

Similar variants

ABCB11 p.Phe508= Likely benign ★ same residue
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+3A>C Pathogenic/Likely pathogenic ★★ same condition
ABCB11 c.2011+1G>T Likely pathogenic ★★ same condition
ABCB11 c.2012-8T>G 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-phe508ser (accessed [today's date]).

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