Is APOA4 p.Val46Met (c.136G>A) pathogenic?

APOA4 p.Val46Met (c.136G>A) is classified Uncertain significance in APOA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-19). AlphaMissense: likely benign (0.1666); Ultra-rare (popmax 0.0165%, mid).

How common is APOA4 p.Val46Met (c.136G>A) in the general population?

APOA4 p.Val46Met (c.136G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about APOA4 p.Val46Met (c.136G>A)?

AlphaMissense predicts likely benign (score 0.1666) — an in-silico prediction, not a clinical call.

APOA4 p.Val46Met

c.136G>A · rs778322182 · VCV1955084

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1666 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1666	likely benign
REVEL	0.285	benign-leaning
SaProt	LLR -7.77	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 0.35	GERP 3.8, phastCons 0.026
Regional constraint	o/e 1.08	unconstrained · MANE · 2,321 bp · p 0.088 · regional, not allelic
Overall
CADD	20.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000619% 10/1,614,240 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
East Asian	0.00446%	22,445
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
South Asian	0.0022%	45,543
European (non-Finnish)	0.000339%	295,012

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.Val46Met
Coding: c.136G>A
MANE Select: NM_000482
dbSNP: rs778322182
Type: single nucleotide variant
Location: chr11:116822699 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.14 · 2 PDB
Residue 46: the '13 x 22 aa approximate tandem repeats' region

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-val46met (accessed [today's date]).

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