Is ABCG8 p.Ser581Arg (c.1743C>A) pathogenic?

ABCG8 p.Ser581Arg (c.1743C>A) is classified Uncertain significance in ABCG8 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.1451); Very rare (popmax 0.00333%, amr); Associated with sitosterolemia 1.

What condition is associated with ABCG8 p.Ser581Arg (c.1743C>A)?

ABCG8 p.Ser581Arg (c.1743C>A) is associated with sitosterolemia 1 (ClinVar).

How common is ABCG8 p.Ser581Arg (c.1743C>A) in the general population?

ABCG8 p.Ser581Arg (c.1743C>A) is very rare (popmax 0.00333%, amr) (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 ABCG8 p.Ser581Arg (c.1743C>A)?

AlphaMissense predicts likely benign (score 0.1451) — an in-silico prediction, not a clinical call.

ABCG8 p.Ser581Arg

c.1743C>A · rs750730480 · VCV899331

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1451 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

sitosterolemia 1

Computational evidence

Protein change
AlphaMissense	0.1451	likely benign
REVEL	0.143	moderately benign-leaning
SaProt	LLR -6.03	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 0.076	GERP -1.8, phastCons 0.7
Regional constraint	o/e 1.29	unconstrained · MANE · 39 kb · p 8.8e-18 · regional, not allelic
Overall
CADD	10.15	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,016 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000867% 14/1,613,890 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,008
European (non-Finnish)	0.00102%	98,335

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: ABCG8
Protein: p.Ser581Arg
Coding: c.1743C>A
MANE Select: NM_022437
dbSNP: rs750730480
Type: single nucleotide variant
Location: chr2:43875400 (GRCh38)
Gene constraint: LOEUF 1.329 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.94 · 8 PDB
Residue 581: the abc transmembrane type-2 domain; a turn

Full ABCG8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

sitosterolemia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Sitosterolemia (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

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ABCG8 p.Arg412Ter Pathogenic/Likely pathogenic ★★ same condition
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ABCG8 p.Trp361Ter 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/abcg8-p-ser581arg (accessed [today's date]).

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