Is ABCB11 p.Leu50Ser (c.149T>C) pathogenic?

ABCB11 p.Leu50Ser (c.149T>C) is classified Conflicting classifications of pathogenicity in ABCB11 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-04-14). AlphaMissense: likely pathogenic (0.9029); Very rare (popmax 0.00161%, nfe); Associated with familial intrahepatic cholestasis.

What condition is associated with ABCB11 p.Leu50Ser (c.149T>C)?

ABCB11 p.Leu50Ser (c.149T>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.Leu50Ser (c.149T>C) in the general population?

ABCB11 p.Leu50Ser (c.149T>C) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about ABCB11 p.Leu50Ser (c.149T>C)?

AlphaMissense predicts likely pathogenic (score 0.9029) — an in-silico prediction, not a clinical call.

ABCB11 p.Leu50Ser

c.149T>C · rs771468316 · VCV3240374

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9029 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial intrahepatic cholestasis

Computational evidence

Protein change
AlphaMissense	0.9029	likely pathogenic · top 10% in ABCB11
REVEL	0.755	pathogenic-leaning
SaProt	LLR -14.31	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.23	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Overall
CADD	33.0	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 0.00161% European (non-Finnish) · 19/1,179,096 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00137% 20/1,460,666 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00161%	62,058
Remaining individualsnot grpmax-eligible	0.0016%	62,442

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.Leu50Ser
Coding: c.149T>C
MANE Select: NM_003742
dbSNP: rs771468316
Type: single nucleotide variant
Location: chr2:169014304 (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 50: a turn

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

Similar variants

ABCB11 p.Leu50Trp Uncertain significance ★ ⚠ same residue
ABCB11 p.Leu50= 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-leu50ser (accessed [today's date]).

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