Is APOA4 p.Val336= (c.1008G>T) pathogenic?

APOA4 p.Val336= (c.1008G>T) is classified Benign in APOA4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-14). Common (popmax 7.68%, afr) — too common for a highly-penetrant pathogenic allele.

APOA4 p.Val336=

Q: How common is APOA4 p.Val336= (c.1008G>T) in the general population?

APOA4 p.Val336= (c.1008G>T) is common (popmax 7.68%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1008G>T · rs5109 · VCV788568

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 7.68%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 2.7, phastCons 0.92
Overall
CADD	8.899	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.68% African / African-American · 5,765/75,036 alleles

Filtering AF 7.52% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.45%

Overall 0.411% 6,630/1,614,188 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.68%	13
Remaining individualsnot grpmax-eligible	0.606%	165
Admixed American	0.555%	180
Middle Eastern	0.396%	252
South Asian	0.0187%	5,358
European (non-Finnish)	0.00949%	10,536

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.Val336=
Coding: c.1008G>T
MANE Select: NM_000482
dbSNP: rs5109
Type: single nucleotide variant
Location: chr11:116821050 (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.Val336Met Conflicting classifications of pathogenicity ★ ⚠ 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-val336 (accessed [today's date]).

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