Is ABCB11 p.Arg1128Ser (c.3382C>A) pathogenic?

ABCB11 p.Arg1128Ser (c.3382C>A) is classified Conflicting classifications of pathogenicity in ABCB11 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-05-30). AlphaMissense: likely pathogenic (0.978); Absent from gnomAD v4.1; Associated with progressive familial intrahepatic cholestasis type 2.

What condition is associated with ABCB11 p.Arg1128Ser (c.3382C>A)?

ABCB11 p.Arg1128Ser (c.3382C>A) is associated with progressive familial intrahepatic cholestasis type 2, benign recurrent intrahepatic cholestasis type 2 (ClinVar).

How common is ABCB11 p.Arg1128Ser (c.3382C>A) in the general population?

ABCB11 p.Arg1128Ser (c.3382C>A) is absent from gnomAD v4.1 (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.Arg1128Ser (c.3382C>A)?

AlphaMissense predicts likely pathogenic (score 0.978) — an in-silico prediction, not a clinical call.

ABCB11 p.Arg1128Ser

c.3382C>A · VCV3336324

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.978 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,576,442)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

progressive familial intrahepatic cholestasis type 2

Computational evidence

Protein change
AlphaMissense	0.978	likely pathogenic · top 3% in ABCB11
REVEL	0.831	moderately pathogenic-leaning
SaProt	LLR -15.61	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.3	GERP 2.1, phastCons 1
Overall
CADD	27.5	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

No allele count reported in gnomAD v4.1 (AN 1,576,442). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ABCB11
Protein: p.Arg1128Ser
Coding: c.3382C>A
MANE Select: NM_003742
Type: single nucleotide variant
Location: chr2:168930694 (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 1128: a turn; the abc transporter 2 domain; a UniProt-annotated variant site (in bric2)

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

Also linked: benign recurrent intrahepatic cholestasis type 2

For Progressive familial intrahepatic cholestasis (Orphanet):

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

Similar variants

ABCB11 p.Arg1128Cys Pathogenic ★★ ⚠ same residue
ABCB11 p.Arg1128Gly Pathogenic/Likely pathogenic ★★ same residue
ABCB11 p.Arg1128His Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCB11 p.Arg1128Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCB11 p.Arg1128Leu Uncertain significance ★ ⚠ same residue
ABCB11 p.Arg1128= Likely benign ★ same residue
ABCB11 c.1084-2A>G Pathogenic ★★ same condition
ABCB11 c.1198-1G>C 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/abcb11-p-arg1128ser (accessed [today's date]).

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