Is ABCG5 p.Ser141Arg (c.421A>C) pathogenic?

ABCG5 p.Ser141Arg (c.421A>C) is classified Uncertain significance in ABCG5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-22). AlphaMissense: ambiguous (0.5271); Absent from gnomAD v4.1; Associated with sitosterolemia.

What condition is associated with ABCG5 p.Ser141Arg (c.421A>C)?

ABCG5 p.Ser141Arg (c.421A>C) is associated with sitosterolemia (ClinVar).

How common is ABCG5 p.Ser141Arg (c.421A>C) in the general population?

ABCG5 p.Ser141Arg (c.421A>C) is absent from gnomAD v4.1 (gnomAD).

How is Sitosterolemia inherited?

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

What do computational predictors say about ABCG5 p.Ser141Arg (c.421A>C)?

AlphaMissense predicts ambiguous (score 0.5271) — an in-silico prediction, not a clinical call.

ABCG5 p.Ser141Arg

c.421A>C · rs2466091244 · VCV2745841

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5271 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

sitosterolemia

Computational evidence

Protein change
AlphaMissense	0.5271	ambiguous
REVEL	0.245	benign-leaning
SaProt	LLR -8.97	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 0.67, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 26 kb · p 0.0064 · regional, not allelic
Overall
CADD	20.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ABCG5
Protein: p.Ser141Arg
Coding: c.421A>C
MANE Select: NM_022436
dbSNP: rs2466091244
Type: single nucleotide variant
Location: chr2:43831849 (GRCh38)
Gene constraint: LOEUF 1.219 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.48 · 8 PDB
Residue 141: the abc transporter domain; a β-strand

Full ABCG5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Sitosterolemia (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

ABCG5 c.1762+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCG5 c.634+1G>C Likely pathogenic ★★ same condition
ABCG5 c.904+1G>A Pathogenic ★★ same condition
ABCG5 p.Arg183Ter Pathogenic/Likely pathogenic ★★ same condition
ABCG5 p.Arg243Ter Pathogenic ★★ same condition
ABCG5 p.Arg389His Pathogenic/Likely pathogenic ★★ same condition
ABCG5 p.Arg408Ter Pathogenic/Likely pathogenic ★★ same condition
ABCG5 p.Arg419His 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/abcg5-p-ser141arg (accessed [today's date]).

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