Is ABCG8 p.Pro317Thr (c.949C>A) pathogenic?

ABCG8 p.Pro317Thr (c.949C>A) is classified Uncertain significance in ABCG8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-25). AlphaMissense: ambiguous (0.5617); Very rare (popmax 0.00167%, amr); Associated with Cardiovascular phenotype.

What condition is associated with ABCG8 p.Pro317Thr (c.949C>A)?

ABCG8 p.Pro317Thr (c.949C>A) is associated with Cardiovascular phenotype (ClinVar).

How common is ABCG8 p.Pro317Thr (c.949C>A) in the general population?

ABCG8 p.Pro317Thr (c.949C>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ABCG8 p.Pro317Thr (c.949C>A)?

AlphaMissense predicts ambiguous (score 0.5617) — an in-silico prediction, not a clinical call.

ABCG8 p.Pro317Thr

c.949C>A · rs762542767 · VCV501340

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5617 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.5617	ambiguous
REVEL	0.789	moderately pathogenic-leaning
SaProt	LLR -14.17	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 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 39 kb · p 8.8e-18 · regional, not allelic
Overall
CADD	27.6	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 0.00167% Admixed American · 1/60,006 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000867% 14/1,613,998 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,006
Remaining individualsnot grpmax-eligible	0.0016%	62,488
African / African-American	0.00134%	74,892
European (non-Finnish)	0.000932%	107,278

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.Pro317Thr
Coding: c.949C>A
MANE Select: NM_022437
dbSNP: rs762542767
Type: single nucleotide variant
Location: chr2:43852853 (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 317: an α-helix

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

Disease context

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

Similar variants

ABCG8 p.Arg121Ter Pathogenic ★★ same condition
ABCG8 p.Arg405Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
ABCG8 p.Gln271Ter Pathogenic/Likely pathogenic ★★ same condition
ABCG8 p.Ala248Thr Uncertain significance ★★ ⚠ same condition
ABCG8 p.Ala346Thr Uncertain significance ★★ ⚠ same condition
ABCG8 p.Ala449Val Uncertain significance ★★ ⚠ same condition
ABCG8 p.Ala450Thr Uncertain significance ★★ ⚠ same condition
ABCG8 p.Ala506Ser Uncertain significance ★★ ⚠ 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-pro317thr (accessed [today's date]).

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