Is APOA5 p.Arg289Cys (c.865C>T) pathogenic?

APOA5 p.Arg289Cys (c.865C>T) is classified Uncertain significance in APOA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-04). AlphaMissense: likely benign (0.1978); Very rare (popmax 0.00333%, amr).

How common is APOA5 p.Arg289Cys (c.865C>T) in the general population?

APOA5 p.Arg289Cys (c.865C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about APOA5 p.Arg289Cys (c.865C>T)?

AlphaMissense predicts likely benign (score 0.1978) — an in-silico prediction, not a clinical call.

APOA5 p.Arg289Cys

c.865C>T · rs755003082 · VCV1686455

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1978 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1978	likely benign
REVEL	0.8	moderately pathogenic-leaning
SaProt	LLR -8.45	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 3, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 1,729 bp · p 0.086 · regional, not allelic
Overall
CADD	31.0	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 0.00333% Admixed American · 2/60,010 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000868% 14/1,613,466 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,005
Remaining individualsnot grpmax-eligible	0.0016%	62,490
African / African-American	0.00133%	74,950
South Asian	0.0011%	91,090
European (non-Finnish)	0.000763%	131,117

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.Arg289Cys
Coding: c.865C>T
MANE Select: NM_001371904
dbSNP: rs755003082
Type: single nucleotide variant
Location: chr11:116790364 (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

Similar variants

APOA5 p.Gln97Ter Pathogenic ★★ same type
APOA5 c.161+3G>A Uncertain significance ★★ same type
APOA5 c.161+5G>C Uncertain significance ★★ same type
APOA5 p.Ala105Ser Uncertain significance ★★ ⚠ same type
APOA5 p.Ala244Ser Uncertain significance ★★ ⚠ same type
APOA5 p.Ala302Val Uncertain significance ★★ ⚠ same type
APOA5 p.Ala82Val Uncertain significance ★★ ⚠ same type
APOA5 p.Arg143His 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/apoa5-p-arg289cys (accessed [today's date]).

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