Is ABCG8 p.Phe494Ser (c.1481T>C) pathogenic?

ABCG8 p.Phe494Ser (c.1481T>C) is classified Uncertain significance in ABCG8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-30). AlphaMissense: likely benign (0.1841); Very rare (popmax 0.00167%, amr); Associated with Cardiovascular phenotype.

What condition is associated with ABCG8 p.Phe494Ser (c.1481T>C)?

ABCG8 p.Phe494Ser (c.1481T>C) is associated with Cardiovascular phenotype, sitosterolemia 1 (ClinVar).

How common is ABCG8 p.Phe494Ser (c.1481T>C) in the general population?

ABCG8 p.Phe494Ser (c.1481T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ABCG8 p.Phe494Ser (c.1481T>C)?

AlphaMissense predicts likely benign (score 0.1841) — an in-silico prediction, not a clinical call.

ABCG8 p.Phe494Ser

c.1481T>C · rs1669891030 · VCV1773581

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1841 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1841	likely benign
REVEL	0.536	indeterminate
SaProt	LLR -8.71	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 1.7, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 39 kb · p 8.8e-18 · regional, not allelic
Overall
CADD	24.2	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 0.00167% Admixed American · 1/59,828 alleles

Overall 0.000124% 2/1,612,572 alleles · very rare exomes 1/1,461,440 · genomes 1/151,132 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,828
Remaining individualsnot grpmax-eligible	0.0016%	62,450

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.Phe494Ser
Coding: c.1481T>C
MANE Select: NM_022437
dbSNP: rs1669891030
Type: single nucleotide variant
Location: chr2:43874476 (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 494: 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 p.Phe494Cys Uncertain significance ★ ⚠ same residue
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

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-phe494ser (accessed [today's date]).

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