Is APOA4 p.Thr367Ser (c.1099A>T) pathogenic?

APOA4 p.Thr367Ser (c.1099A>T) is classified Benign in APOA4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0813); Common (popmax 24.2%, mid) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about APOA4 p.Thr367Ser (c.1099A>T)?

AlphaMissense predicts likely benign (score 0.0813) — an in-silico prediction, not a clinical call.

APOA4 p.Thr367Ser

Q: How common is APOA4 p.Thr367Ser (c.1099A>T) in the general population?

APOA4 p.Thr367Ser (c.1099A>T) is common (popmax 24.2%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1099A>T · rs675 · VCV1245704

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0813 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 24.2%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0813	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -5.81	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 0.24	GERP -0.72
Regional constraint	o/e 1.08	unconstrained · MANE · 2,321 bp · p 0.088 · regional, not allelic
Overall
CADD	5.582	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 24.2% Middle Eastern · 1,466/6,062 alleles

Filtering AF 23.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 22.7%

Overall 17.8% 286,754/1,613,684 alleles · common

Ancestry group	Frequency	1 in
Middle Easterngrpmax	24.2%	4
Amishnot grpmax-eligible	23.4%	4
Ashkenazi Jewishnot grpmax-eligible	21.4%	5
European (non-Finnish)	19.6%	5
Remaining individualsnot grpmax-eligible	17.5%	6
Finnishnot grpmax-eligible	14.1%	7
South Asian	13.3%	8
African / African-American	11.5%	9
Admixed American	10.8%	9
East Asian	0.0557%	1,794

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.Thr367Ser
Coding: c.1099A>T
MANE Select: NM_000482
dbSNP: rs675
Type: single nucleotide variant
Location: chr11:116820959 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.14 · 2 PDB
Residue 367: the 'disordered' region; a UniProt-annotated variant site (in allele apoa-iv*1a and allele budapest-1)

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

Similar variants

APOA4 p.Thr367Ala 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
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-thr367ser (accessed [today's date]).

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