What condition is associated with ABCB4 p.Gln1246Pro (c.3737A>C)?

ABCB4 p.Gln1246Pro (c.3737A>C) is associated with progressive familial intrahepatic cholestasis type 3 (ClinVar).

How common is ABCB4 p.Gln1246Pro (c.3737A>C) in the general population?

ABCB4 p.Gln1246Pro (c.3737A>C) is very rare (popmax 0.0011%, sas) (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.Gln1246Pro (c.3737A>C)?

AlphaMissense predicts likely pathogenic (score 0.7797) — an in-silico prediction, not a clinical call.

ABCB4 p.Gln1246Pro

Q: Is ABCB4 p.Gln1246Pro (c.3737A>C) pathogenic?

ABCB4 p.Gln1246Pro (c.3737A>C) is classified Uncertain significance in ABCB4 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.7797); Very rare (popmax 0.0011%, sas); Associated with progressive familial intrahepatic cholestasis type 3.

c.3737A>C · rs2546735713 · VCV2584796

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7797 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

progressive familial intrahepatic cholestasis type 3

Computational evidence

Protein change
AlphaMissense	0.7797	likely pathogenic
REVEL	0.534	indeterminate
SaProt	LLR -14.26	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 183 bp · p 0.039 · regional, not allelic
Overall
CADD	24.4	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM Q1253P vs ClinVar Q1246P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,076 alleles

Overall 6.84e-05% 1/1,461,814 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.Gln1246Pro
Coding: c.3737A>C
MANE Select: NM_000443
dbSNP: rs2546735713
Type: single nucleotide variant
Location: chr7:87402199 (GRCh38)
Gene constraint: LOEUF 0.623 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 83.36 · 4 PDB
Residue 1246: 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

For Progressive familial intrahepatic cholestasis (Orphanet):

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

Similar variants

ABCB4 c.1560+1G>A 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.3081+1G>C Pathogenic ★★ same condition
ABCB4 c.3486+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCB4 c.834-1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCB4 p.Arg1046Ter Pathogenic/Likely pathogenic ★★ same condition
ABCB4 p.Arg144Ter 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-gln1246pro (accessed [today's date]).

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