Is APOA4 p.Ala161Ser (c.481G>T) pathogenic?

APOA4 p.Ala161Ser (c.481G>T) is classified Benign in APOA4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1079); Low-frequency (popmax 1.13%, nfe).

How common is APOA4 p.Ala161Ser (c.481G>T) in the general population?

APOA4 p.Ala161Ser (c.481G>T) is low-frequency (popmax 1.13%, nfe) (gnomAD).

What do computational predictors say about APOA4 p.Ala161Ser (c.481G>T)?

AlphaMissense predicts likely benign (score 0.1079) — an in-silico prediction, not a clinical call.

APOA4 p.Ala161Ser

c.481G>T · rs12721043 · VCV1601220

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1079 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.13%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1079	likely benign
REVEL	0.204	benign-leaning
SaProt	LLR -8.21	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 -0.92	GERP 0.21
Regional constraint	o/e 1.08	unconstrained · MANE · 2,321 bp · p 0.088 · regional, not allelic
Overall
CADD	2.623	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 1.13% European (non-Finnish) · 13,329/1,179,624 alleles

Filtering AF 1.11% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.11%

Overall 0.936% 15,085/1,610,928 alleles · low-frequency

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.13%	89
Finnishnot grpmax-eligible	0.907%	110
Remaining individualsnot grpmax-eligible	0.767%	130
Middle Eastern	0.545%	184
Admixed American	0.433%	231
Ashkenazi Jewishnot grpmax-eligible	0.348%	287
African / African-American	0.205%	487
South Asian	0.187%	536
East Asian	0.00223%	44,858

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.Ala161Ser
Coding: c.481G>T
MANE Select: NM_000482
dbSNP: rs12721043
Type: single nucleotide variant
Location: chr11:116821577 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.14 · 2 PDB
Residue 161: the '13 x 22 aa approximate tandem repeats' region; a UniProt-annotated variant site (in seattle-3); an α-helix

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

Similar variants

APOA4 p.Ala161Thr Uncertain significance ★ ⚠ same residue
APOA4 p.Ala161Val Uncertain significance ★ ⚠ same residue
APOA4 p.Ala161= Likely benign ★ 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

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-ala161ser (accessed [today's date]).

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