Is ABCG8 p.Phe562Leu (c.1686C>A) pathogenic?

ABCG8 p.Phe562Leu (c.1686C>A) is classified Likely benign in ABCG8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-18). AlphaMissense: likely benign (0.272); Very rare (popmax 0.00133%, afr); Associated with Cardiovascular phenotype.

What condition is associated with ABCG8 p.Phe562Leu (c.1686C>A)?

ABCG8 p.Phe562Leu (c.1686C>A) is associated with Cardiovascular phenotype (ClinVar).

How common is ABCG8 p.Phe562Leu (c.1686C>A) in the general population?

ABCG8 p.Phe562Leu (c.1686C>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ABCG8 p.Phe562Leu (c.1686C>A)?

AlphaMissense predicts likely benign (score 0.272) — an in-silico prediction, not a clinical call.

ABCG8 p.Phe562Leu

c.1686C>A · VCV3313083

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.272 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.272	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -5.95	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 -2.4	GERP -2.9
Regional constraint	o/e 1.29	unconstrained · MANE · 39 kb · p 8.8e-18 · regional, not allelic
Overall
CADD	5.541	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 0.00133% African / African-American · 1/74,942 alleles

Overall 0.000657% 1/152,220 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.Phe562Leu
Coding: c.1686C>A
MANE Select: NM_022437
Type: single nucleotide variant
Location: chr2:43875343 (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 562: 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

Similar variants

ABCG8 p.Phe562Ser Uncertain significance ★ ⚠ same residue
ABCG8 p.Phe562= Likely benign ★ same residue
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

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-phe562leu (accessed [today's date]).

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