Is ABCB4 p.Leu1065Val (c.3193C>G) pathogenic?

ABCB4 p.Leu1065Val (c.3193C>G) is classified Uncertain significance in ABCB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-14). AlphaMissense: likely benign (0.0643); Very rare (popmax 0.00133%, afr); Associated with progressive familial intrahepatic cholestasis type 3.

How common is ABCB4 p.Leu1065Val (c.3193C>G) in the general population?

ABCB4 p.Leu1065Val (c.3193C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

How is Progressive familial intrahepatic cholestasis inherited?

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

What do computational predictors say about ABCB4 p.Leu1065Val (c.3193C>G)?

AlphaMissense predicts likely benign (score 0.0643) — an in-silico prediction, not a clinical call.

ABCB4 p.Leu1065Val

Q: What condition is associated with ABCB4 p.Leu1065Val (c.3193C>G)?

ABCB4 p.Leu1065Val (c.3193C>G) is associated with progressive familial intrahepatic cholestasis type 3, familial intrahepatic cholestasis (ClinVar).

c.3193C>G · rs779141589 · VCV2663955

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0643 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

progressive familial intrahepatic cholestasis type 3

Computational evidence

Protein change
AlphaMissense	0.0643	likely benign
REVEL	0.303	indeterminate
SaProt	LLR -2.77	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 3.9	GERP 0.14, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 14 kb · p 8.2e-06 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00133% African / African-American · 1/75,070 alleles

Overall 6.84e-05% 1/1,461,872 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: ABCB4
Protein: p.Leu1065Val
Coding: c.3193C>G
MANE Select: NM_000443
dbSNP: rs779141589
Type: single nucleotide variant
Location: chr7:87408123 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 1065: a β-strand; the abc transporter 2 domain

Full ABCB4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

progressive familial intrahepatic cholestasis type 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial intrahepatic cholestasis

For Progressive familial intrahepatic cholestasis (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Childhood, Infancy, Neonatal

Similar variants

ABCB4 p.Leu1065= Likely benign ★ same residue
ABCB4 c.1560+1G>A Likely pathogenic ★★ same condition
ABCB4 c.2064+3A>T Likely pathogenic ★★ same condition
ABCB4 c.2211+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.2682+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.2783+1G>T Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.286+1G>A Pathogenic ★★ same condition
ABCB4 c.3081+1G>C 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/abcb4-p-leu1065val (accessed [today's date]).

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