Is ABCG8 p.Pro231Thr (c.691C>A) pathogenic?

ABCG8 p.Pro231Thr (c.691C>A) is classified Uncertain significance in ABCG8 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-11-01). AlphaMissense: ambiguous (0.5637); Very rare (popmax 8.48e-05%, nfe); Associated with sitosterolemia 1.

What condition is associated with ABCG8 p.Pro231Thr (c.691C>A)?

ABCG8 p.Pro231Thr (c.691C>A) is associated with sitosterolemia 1 (ClinVar).

How common is ABCG8 p.Pro231Thr (c.691C>A) in the general population?

ABCG8 p.Pro231Thr (c.691C>A) is very rare (popmax 8.48e-05%, nfe) (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.Pro231Thr (c.691C>A)?

AlphaMissense predicts ambiguous (score 0.5637) — an in-silico prediction, not a clinical call.

ABCG8 p.Pro231Thr

c.691C>A · rs137852993 · VCV4974

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5637 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

sitosterolemia 1

Computational evidence

Protein change
AlphaMissense	0.5637	ambiguous
REVEL	0.72	pathogenic-leaning
SaProt	LLR -12.77	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 39 kb · p 8.8e-18 · regional, not allelic
Overall
CADD	27.3	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 8.48e-05% European (non-Finnish) · 1/1,179,884 alleles

Overall 6.84e-05% 1/1,461,234 alleles · very rare

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.Pro231Thr
Coding: c.691C>A
MANE Select: NM_022437
dbSNP: rs137852993
Type: single nucleotide variant
Location: chr2:43852483 (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 231: the abc transporter domain; a UniProt-annotated variant site (in stsl1; strongly decreased maturation of glycan chains)

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

Similar variants

ABCG8 p.Pro231Gln Uncertain significance ★ ⚠ same residue
ABCG8 c.64-2A>G Pathogenic ★★ same condition
ABCG8 c.965-1G>C Pathogenic ★★ same condition
ABCG8 p.Arg164Ter Pathogenic ★★ same condition
ABCG8 p.Arg405Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
ABCG8 p.Arg412Ter Pathogenic/Likely pathogenic ★★ same condition
ABCG8 p.Gly574Arg Pathogenic/Likely pathogenic ★★ same condition
ABCG8 p.Ser107Ter 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-pro231thr (accessed [today's date]).

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