Is APOA5 p.Arg94Pro (c.281G>C) pathogenic?

APOA5 p.Arg94Pro (c.281G>C) is classified Uncertain significance in APOA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: likely benign (0.2104); Very rare (popmax 0.00133%, afr); Associated with Cardiovascular phenotype.

What condition is associated with APOA5 p.Arg94Pro (c.281G>C)?

APOA5 p.Arg94Pro (c.281G>C) is associated with Cardiovascular phenotype (ClinVar).

How common is APOA5 p.Arg94Pro (c.281G>C) in the general population?

APOA5 p.Arg94Pro (c.281G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about APOA5 p.Arg94Pro (c.281G>C)?

AlphaMissense predicts likely benign (score 0.2104) — an in-silico prediction, not a clinical call.

APOA5 p.Arg94Pro

c.281G>C · rs778302124 · VCV3127895

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2104 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2104	likely benign
REVEL	0.119	moderately benign-leaning
SaProt	LLR -9.34	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 -0.15	GERP 2.1, phastCons 0.71
Regional constraint	o/e 0.92	unconstrained · MANE · 1,729 bp · p 0.086 · regional, not allelic
Overall
CADD	20.1	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 0.00133% African / African-American · 1/74,940 alleles

Overall 6.2e-05% 1/1,613,120 alleles · very rare exomes 0/1,460,912 · genomes 1/152,208 · joint denominator

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: APOA5
Protein: p.Arg94Pro
Coding: c.281G>C
MANE Select: NM_001371904
dbSNP: rs778302124
Type: single nucleotide variant
Location: chr11:116790948 (GRCh38)
Gene constraint: LOEUF 1.146 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.38

Full APOA5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

APOA5 p.Arg94Gln Likely benign ★ same residue
APOA5 p.Arg94Trp Uncertain significance ★★ ⚠ same residue
APOA5 c.161+3G>A Uncertain significance ★★ same condition
APOA5 c.161+5G>C Uncertain significance ★★ same condition
APOA5 p.Ala244Ser Uncertain significance ★★ ⚠ same condition
APOA5 p.Ala302Val Uncertain significance ★★ ⚠ same condition
APOA5 p.Ala82Val Uncertain significance ★★ ⚠ same condition
APOA5 p.Arg226Cys Uncertain significance ★★ ⚠ same condition

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/apoa5-p-arg94pro (accessed [today's date]).

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