Is APOA4 p.Arg264Trp (c.790C>T) pathogenic?

APOA4 p.Arg264Trp (c.790C>T) is classified Uncertain significance in APOA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-04). AlphaMissense: likely benign (0.1564); Ultra-rare (popmax 0.0165%, mid).

How common is APOA4 p.Arg264Trp (c.790C>T) in the general population?

APOA4 p.Arg264Trp (c.790C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about APOA4 p.Arg264Trp (c.790C>T)?

AlphaMissense predicts likely benign (score 0.1564) — an in-silico prediction, not a clinical call.

APOA4 p.Arg264Trp

c.790C>T · rs747989886 · VCV2367692

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1564 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1564	likely benign
REVEL	0.292	indeterminate
SaProt	LLR -13.97	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.2, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 2,321 bp · p 0.088 · regional, not allelic
Overall
CADD	22.3	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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.00285% 46/1,613,392 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
South Asian	0.0121%	8,280
East Asian	0.00891%	11,218
Remaining individualsnot grpmax-eligible	0.0032%	31,249
African / African-American	0.00266%	37,529
European (non-Finnish)	0.00212%	47,201
Admixed American	0.00167%	60,036

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.Arg264Trp
Coding: c.790C>T
MANE Select: NM_000482
dbSNP: rs747989886
Type: single nucleotide variant
Location: chr11:116821268 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.14 · 2 PDB
Residue 264: the '13 x 22 aa approximate tandem repeats' region; a UniProt-annotated variant site (in seattle-2; may contribute to the development of familial combined hyperlipidemia); an α-helix

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

Similar variants

APOA4 p.Arg264Gln Uncertain significance ★ ⚠ same residue
APOA4 p.Arg264= 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
APOA4 p.Gln50Arg 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-arg264trp (accessed [today's date]).

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