Is ABCB11 p.Asn375Ser (c.1124A>G) pathogenic?

ABCB11 p.Asn375Ser (c.1124A>G) is classified Likely benign in ABCB11 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-03). AlphaMissense: likely benign (0.0757); Rare (popmax 0.51%, sas); Associated with progressive familial intrahepatic cholestasis type 2.

What condition is associated with ABCB11 p.Asn375Ser (c.1124A>G)?

ABCB11 p.Asn375Ser (c.1124A>G) is associated with progressive familial intrahepatic cholestasis type 2 (ClinVar).

How common is ABCB11 p.Asn375Ser (c.1124A>G) in the general population?

ABCB11 p.Asn375Ser (c.1124A>G) is rare (popmax 0.51%, 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 ABCB11 p.Asn375Ser (c.1124A>G)?

AlphaMissense predicts likely benign (score 0.0757) — an in-silico prediction, not a clinical call.

ABCB11 p.Asn375Ser

c.1124A>G · rs572222881 · VCV332035

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0757 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.51%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

progressive familial intrahepatic cholestasis type 2

Computational evidence

Protein change
AlphaMissense	0.0757	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -5.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 0.9, phastCons 0.99
Overall
CADD	22.3	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 0.51% South Asian · 464/90,990 alleles

Filtering AF 0.472% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.456%

Overall 0.0313% 503/1,607,094 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.51%	196
Middle Eastern	0.0331%	3,022
Remaining individualsnot grpmax-eligible	0.0322%	3,103
European (non-Finnish)	0.00145%	69,141

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.Asn375Ser
Coding: c.1124A>G
MANE Select: NM_003742
dbSNP: rs572222881
Type: single nucleotide variant
Location: chr2:168979939 (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 375: an α-helix; the abc transmembrane type-1 1 domain

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 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
ABCB11 c.150+2T>C Pathogenic/Likely pathogenic ★★ same condition
ABCB11 c.150+3A>C Pathogenic/Likely pathogenic ★★ same condition
ABCB11 c.1638+1G>C Likely pathogenic ★★ same condition
ABCB11 c.1810-1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCB11 c.2011+1G>T 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-asn375ser (accessed [today's date]).

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