Is APOA1 p.Ala4= (c.12G>A) pathogenic?

APOA1 p.Ala4= (c.12G>A) is classified Likely benign in APOA1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-19). Very rare (popmax 0.0058%, amr); Associated with Cardiovascular phenotype.

What condition is associated with APOA1 p.Ala4= (c.12G>A)?

APOA1 p.Ala4= (c.12G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is APOA1 p.Ala4= (c.12G>A) in the general population?

APOA1 p.Ala4= (c.12G>A) is very rare (popmax 0.0058%, amr) (gnomAD).

APOA1 p.Ala4=

c.12G>A · rs368534370 · VCV1478526

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0058%, amr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.012	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.2	GERP 2.5
Overall
CADD	9.917	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0058% Admixed American · 3/51,732 alleles

Filtering AF 0.00367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00329%

Overall 0.00404% 63/1,561,122 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0058%	17,244
Remaining individualsnot grpmax-eligible	0.00496%	20,163
European (non-Finnish)	0.00469%	21,336
South Asian	0.00235%	42,493
African / African-American	0.00136%	73,754

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: APOA1
Protein: p.Ala4=
Coding: c.12G>A
MANE Select: NM_000039
dbSNP: rs368534370
Type: single nucleotide variant
Location: chr11:116837376 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.66 · 31 PDB

Full APOA1 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

APOA1 p.Ala4Val Uncertain significance ★★ ⚠ same residue
APOA1 p.Ala4Glu Uncertain significance ★ ⚠ same residue
APOA1 p.Ala176Thr Uncertain significance ★★ ⚠ same condition
APOA1 p.Ala176Val Uncertain significance ★★ ⚠ same condition
APOA1 p.Ala204Val Uncertain significance ★★ ⚠ same condition
APOA1 p.Ala218Thr Uncertain significance ★★ ⚠ same condition
APOA1 p.Ala256Thr Uncertain significance ★★ ⚠ same condition
APOA1 p.Arg140Leu 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/apoa1-p-ala4 (accessed [today's date]).

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