Is ABCG8 p.Ala519Ser (c.1555G>T) pathogenic?

ABCG8 p.Ala519Ser (c.1555G>T) is classified Uncertain significance in ABCG8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-23). AlphaMissense: likely benign (0.1518); Very rare (popmax 0.00223%, eas); Associated with Cardiovascular phenotype.

What condition is associated with ABCG8 p.Ala519Ser (c.1555G>T)?

ABCG8 p.Ala519Ser (c.1555G>T) is associated with Cardiovascular phenotype (ClinVar).

How common is ABCG8 p.Ala519Ser (c.1555G>T) in the general population?

ABCG8 p.Ala519Ser (c.1555G>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ABCG8 p.Ala519Ser (c.1555G>T)?

AlphaMissense predicts likely benign (score 0.1518) — an in-silico prediction, not a clinical call.

ABCG8 p.Ala519Ser

c.1555G>T · rs1558859254 · VCV3129918

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1518 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1518	likely benign
REVEL	0.255	benign-leaning
SaProt	LLR -7.47	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 3.4	GERP 0.13, phastCons 1
Regional constraint	o/e 1.29	unconstrained · MANE · 39 kb · p 8.8e-18 · regional, not allelic
Overall
CADD	19.0	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 0.00223% East Asian · 1/44,878 alleles

Overall 6.2e-05% 1/1,614,200 alleles · very rare exomes 1/1,461,864 · genomes 0/152,336 · joint denominator

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.Ala519Ser
Coding: c.1555G>T
MANE Select: NM_022437
dbSNP: rs1558859254
Type: single nucleotide variant
Location: chr2:43875212 (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 519: the abc transmembrane type-2 domain; a turn

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.Ala519Val Uncertain significance ★ ⚠ same residue
ABCG8 p.Ala519= Conflicting classifications of pathogenicity ★ 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-ala519ser (accessed [today's date]).

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