Is APOA4 p.Ser353Ala (c.1057T>G) pathogenic?

APOA4 p.Ser353Ala (c.1057T>G) is classified Benign/Likely benign in APOA4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.0749); Low-frequency (popmax 2.78%, afr).

How common is APOA4 p.Ser353Ala (c.1057T>G) in the general population?

APOA4 p.Ser353Ala (c.1057T>G) is low-frequency (popmax 2.78%, afr) (gnomAD).

What do computational predictors say about APOA4 p.Ser353Ala (c.1057T>G)?

AlphaMissense predicts likely benign (score 0.0749) — an in-silico prediction, not a clinical call.

APOA4 p.Ser353Ala

c.1057T>G · rs146353487 · VCV710015

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0749 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.78%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0749	likely benign
REVEL	0.222	benign-leaning
SaProt	LLR -6.88	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 2.2	GERP 5.3, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 2,321 bp · p 0.088 · regional, not allelic
Overall
CADD	16.45	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 2.78% African / African-American · 2,087/75,030 alleles

Filtering AF 2.68% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.64%

Overall 0.151% 2,444/1,614,190 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.78%	36
Middle Eastern	0.462%	216
Remaining individualsnot grpmax-eligible	0.229%	437
Admixed American	0.197%	509
South Asian	0.0132%	7,590
European (non-Finnish)	0.00475%	21,072

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: APOA4
Protein: p.Ser353Ala
Coding: c.1057T>G
MANE Select: NM_000482
dbSNP: rs146353487
Type: single nucleotide variant
Location: chr11:116821001 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.14 · 2 PDB

Full APOA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APOA4 p.Ser353Phe Uncertain significance ★ ⚠ same residue
APOA4 p.Ala172Thr Uncertain significance ★★ ⚠ same type
APOA4 p.Ala333Val Uncertain significance ★★ ⚠ same type
APOA4 p.Ala60Asp Uncertain significance ★★ ⚠ same type
APOA4 p.Arg166Ser Uncertain significance ★★ ⚠ same type
APOA4 p.Arg275Cys Uncertain significance ★★ ⚠ same type
APOA4 p.Gln50Arg Uncertain significance ★★ ⚠ same type
APOA4 p.Gln50Lys Uncertain significance ★★ ⚠ same type

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/apoa4-p-ser353ala (accessed [today's date]).

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