Is APOA4 p.Pro393Leu (c.1178C>T) pathogenic?

APOA4 p.Pro393Leu (c.1178C>T) is classified Uncertain significance in APOA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-14). AlphaMissense: likely benign (0.1073); Very rare (popmax 0.00729%, nfe).

How common is APOA4 p.Pro393Leu (c.1178C>T) in the general population?

APOA4 p.Pro393Leu (c.1178C>T) is very rare (popmax 0.00729%, nfe) (gnomAD).

What do computational predictors say about APOA4 p.Pro393Leu (c.1178C>T)?

AlphaMissense predicts likely benign (score 0.1073) — an in-silico prediction, not a clinical call.

APOA4 p.Pro393Leu

c.1178C>T · rs1352011550 · VCV2956449

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1073 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00729%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1073	likely benign
REVEL	0.319	indeterminate
SaProt	LLR -7.71	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 7.6, phastCons 0.75
Regional constraint	o/e 1.08	unconstrained · MANE · 2,321 bp · p 0.088 · regional, not allelic
Overall
CADD	18.31	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 0.00729% European (non-Finnish) · 86/1,180,014 alleles

Filtering AF 0.00604% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00557%

Overall 0.00558% 90/1,613,870 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00729%	13,721
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
Remaining individualsnot grpmax-eligible	0.0032%	31,238
Finnishnot grpmax-eligible	0.00156%	63,978

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.Pro393Leu
Coding: c.1178C>T
MANE Select: NM_000482
dbSNP: rs1352011550
Type: single nucleotide variant
Location: chr11:116820880 (GRCh38)
Gene constraint: LOEUF 0.985 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.14 · 2 PDB
Residue 393: the 'disordered' 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-pro393leu (accessed [today's date]).

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