Is ABCB11 p.Arg1153Pro (c.3458G>C) pathogenic?

ABCB11 p.Arg1153Pro (c.3458G>C) is classified Conflicting classifications of pathogenicity in ABCB11 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-02-05). AlphaMissense: likely pathogenic (0.9863); Very rare (popmax 0.000254%, nfe); Associated with progressive familial intrahepatic cholestasis type 2.

What condition is associated with ABCB11 p.Arg1153Pro (c.3458G>C)?

ABCB11 p.Arg1153Pro (c.3458G>C) is associated with progressive familial intrahepatic cholestasis type 2 (ClinVar).

How common is ABCB11 p.Arg1153Pro (c.3458G>C) in the general population?

ABCB11 p.Arg1153Pro (c.3458G>C) is very rare (popmax 0.000254%, nfe) (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 ABCB11 p.Arg1153Pro (c.3458G>C)?

AlphaMissense predicts likely pathogenic (score 0.9863) — an in-silico prediction, not a clinical call.

ABCB11 p.Arg1153Pro

c.3458G>C · VCV3769191

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9863 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

progressive familial intrahepatic cholestasis type 2

Computational evidence

Protein change
AlphaMissense	0.9863	likely pathogenic · top 1% in ABCB11
REVEL	0.967	strongly pathogenic-leaning
SaProt	LLR -17.37	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Overall
CADD	32.0	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 0.000254% European (non-Finnish) · 3/1,179,804 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,613,724 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,458
European (non-Finnish)grpmax	0.000254%	393,267

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg1153Pro
Coding: c.3458G>C
MANE Select: NM_003742
Type: single nucleotide variant
Location: chr2:168927316 (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 1153: an α-helix; the abc transporter 2 domain; a UniProt-annotated variant site (in pfic2; impairs taurocholate transport activity; significantly reduces protein expression; decreases cell surface protein expression; loss of ell membrane localization)

Full ABCB11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

progressive familial intrahepatic cholestasis type 2 — 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

ABCB11 p.Arg1153Cys Pathogenic/Likely pathogenic ★★ ⚠ same residue
ABCB11 p.Arg1153His Pathogenic/Likely pathogenic ★★ same residue
ABCB11 p.Arg1153Leu Likely pathogenic ★ same residue
ABCB11 p.Arg1153Gly Uncertain significance ★ ⚠ same residue
ABCB11 p.Arg1153= Likely benign ★ same residue
ABCB11 c.1084-2A>G Pathogenic ★★ same condition
ABCB11 c.1198-1G>C Pathogenic/Likely pathogenic ★★ same condition
ABCB11 c.1198-2A>C 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-arg1153pro (accessed [today's date]).

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