Is ABCB11 p.Leu617Phe (c.1851G>T) pathogenic?

ABCB11 p.Leu617Phe (c.1851G>T) is classified Uncertain significance in ABCB11 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-14). AlphaMissense: ambiguous (0.3596); Very rare (popmax 0.00017%, nfe); Associated with familial intrahepatic cholestasis.

What condition is associated with ABCB11 p.Leu617Phe (c.1851G>T)?

ABCB11 p.Leu617Phe (c.1851G>T) is associated with familial intrahepatic cholestasis (ClinVar).

How common is ABCB11 p.Leu617Phe (c.1851G>T) in the general population?

ABCB11 p.Leu617Phe (c.1851G>T) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about ABCB11 p.Leu617Phe (c.1851G>T)?

AlphaMissense predicts ambiguous (score 0.3596) — an in-silico prediction, not a clinical call.

ABCB11 p.Leu617Phe

c.1851G>T · VCV3339770

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3596 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

familial intrahepatic cholestasis

Computational evidence

Protein change
AlphaMissense	0.3596	ambiguous
REVEL	0.567	indeterminate
SaProt	LLR -11.81	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.4	GERP -3.9
Overall
CADD	11.74	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 0.00017% European (non-Finnish) · 2/1,179,174 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,460,456 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.Leu617Phe
Coding: c.1851G>T
MANE Select: NM_003742
Type: single nucleotide variant
Location: chr2:168969510 (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 617: a turn; the abc transporter 1 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.Leu617= 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.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-leu617phe (accessed [today's date]).

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