Is ABCG8 p.Pro491= (c.1473A>G) pathogenic?

ABCG8 p.Pro491= (c.1473A>G) is classified Conflicting classifications of pathogenicity in ABCG8 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-10-23). Rare (popmax 0.12%, afr); Associated with Cardiovascular phenotype.

What condition is associated with ABCG8 p.Pro491= (c.1473A>G)?

ABCG8 p.Pro491= (c.1473A>G) is associated with Cardiovascular phenotype, sitosterolemia 1 (ClinVar).

How common is ABCG8 p.Pro491= (c.1473A>G) in the general population?

ABCG8 p.Pro491= (c.1473A>G) is rare (popmax 0.12%, afr) (gnomAD).

ABCG8 p.Pro491=

c.1473A>G · rs146046068 · VCV595020

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.12%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.63	donor gain · deltas
Pangolin	Δ0.26	gain · loss 0.25 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -5.5	GERP -3.5
Overall
CADD	13.59	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.12% African / African-American · 90/74,914 alleles

Filtering AF 0.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0926%

Overall 0.0062% 100/1,613,544 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.12%	832
Middle Eastern	0.0165%	6,060
Remaining individualsnot grpmax-eligible	0.0064%	15,624
Admixed American	0.00334%	29,981
European (non-Finnish)	0.000254%	393,264

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.Pro491=
Coding: c.1473A>G
MANE Select: NM_022437
dbSNP: rs146046068
Type: single nucleotide variant
Location: chr2:43874468 (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 491: the abc transmembrane type-2 domain; 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

Also linked: sitosterolemia 1

Similar variants

ABCG8 c.64-2A>G Pathogenic ★★ same condition
ABCG8 c.965-1G>C Pathogenic ★★ same condition
ABCG8 p.Arg121Ter 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.Gln271Ter Pathogenic/Likely pathogenic ★★ same condition
ABCG8 p.Gly574Arg 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-pro491 (accessed [today's date]).

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