Is APOA4 p.Val6Met (c.16G>A) pathogenic?

APOA4 p.Val6Met (c.16G>A) is classified Uncertain significance in APOA4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-28). AlphaMissense: likely benign (0.2327); Ultra-rare (popmax 0.0613%, nfe).

How common is APOA4 p.Val6Met (c.16G>A) in the general population?

APOA4 p.Val6Met (c.16G>A) is ultra-rare (popmax 0.0613%, nfe) (gnomAD).

What do computational predictors say about APOA4 p.Val6Met (c.16G>A)?

AlphaMissense predicts likely benign (score 0.2327) — an in-silico prediction, not a clinical call.

APOA4 p.Val6Met

c.16G>A · rs148312574 · VCV2138254

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2327 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0613%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2327	likely benign
REVEL	0.342	indeterminate
SaProt	LLR -10.03	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 2.1	GERP 3, phastCons 0.97
Regional constraint	o/e 1.08	unconstrained · MANE · 2,321 bp · p 0.088 · regional, not allelic
Overall
CADD	19.52	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 0.0613% European (non-Finnish) · 723/1,180,022 alleles

Filtering AF 0.0575% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.056%

Overall 0.0476% 768/1,614,114 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0613%	1,632
Remaining individualsnot grpmax-eligible	0.0224%	4,465
Admixed American	0.0183%	5,457
African / African-American	0.0147%	6,823
Finnishnot grpmax-eligible	0.0109%	9,137
East Asian	0.00446%	22,441

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.Val6Met
Coding: c.16G>A
MANE Select: NM_000482
dbSNP: rs148312574
Type: single nucleotide variant
Location: chr11:116823176 (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.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
APOA4 p.Glu283Ala 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-val6met (accessed [today's date]).

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