Is ABCB4 p.Pro1161Ser (c.3481C>T) pathogenic?

ABCB4 p.Pro1161Ser (c.3481C>T) is classified Conflicting classifications of pathogenicity in ABCB4 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-04-14). AlphaMissense: ambiguous (0.4982); Ultra-rare (popmax 0.033%, mid); Associated with gallbladder disease 1.

What condition is associated with ABCB4 p.Pro1161Ser (c.3481C>T)?

ABCB4 p.Pro1161Ser (c.3481C>T) is associated with gallbladder disease 1 (ClinVar).

How common is ABCB4 p.Pro1161Ser (c.3481C>T) in the general population?

ABCB4 p.Pro1161Ser (c.3481C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

How is Low phospholipid-associated cholelithiasis inherited?

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

What do computational predictors say about ABCB4 p.Pro1161Ser (c.3481C>T)?

AlphaMissense predicts ambiguous (score 0.4982) — an in-silico prediction, not a clinical call.

ABCB4 p.Pro1161Ser

c.3481C>T · rs121918442 · VCV13692

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

ambiguous

0.4982 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

gallbladder disease 1

Computational evidence

Protein change
AlphaMissense	0.4982	ambiguous
REVEL	0.873	moderately pathogenic-leaning
SaProt	LLR -9.83	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 14 kb · p 8.2e-06 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P1168S vs ClinVar P1161S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00229% 37/1,614,016 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.0096%	10,417
South Asian	0.00439%	22,768
African / African-American	0.00267%	37,503
European (non-Finnish)	0.00186%	53,634
Admixed American	0.00167%	60,024

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.Pro1161Ser
Coding: c.3481C>T
MANE Select: NM_000443
dbSNP: rs121918442
Type: single nucleotide variant
Location: chr7:87406293 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 1161: a UniProt-annotated variant site (in gbd1); an α-helix; the abc transporter 2 domain

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

Disease context

gallbladder disease 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Low phospholipid-associated cholelithiasis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adult

Similar variants

ABCB4 c.1356+2T>C Pathogenic/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.286+1G>A Pathogenic ★★ same condition
ABCB4 c.3486+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.3486+5G>A Likely pathogenic ★★ same condition
ABCB4 c.80+1G>A Likely pathogenic ★★ same condition
ABCB4 c.834-1G>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/abcb4-p-pro1161ser (accessed [today's date]).

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