Is APOA1 p.Pro31Ala (c.91C>G) pathogenic?

APOA1 p.Pro31Ala (c.91C>G) is classified Uncertain significance in APOA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-21). AlphaMissense: likely benign (0.1487); Very rare (popmax 0.000763%, nfe).

How common is APOA1 p.Pro31Ala (c.91C>G) in the general population?

APOA1 p.Pro31Ala (c.91C>G) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about APOA1 p.Pro31Ala (c.91C>G)?

AlphaMissense predicts likely benign (score 0.1487) — an in-silico prediction, not a clinical call.

APOA1 p.Pro31Ala

c.91C>G · rs764283540 · VCV2985998

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1487 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1487	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -5.83	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 -0.04	GERP -3.4
Regional constraint	o/e 1.01	unconstrained · MANE · 1,576 bp · p 0.87 · regional, not allelic
Overall
CADD	4.127	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 0.000763% European (non-Finnish) · 9/1,179,860 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,613,736 alleles · very rare

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: APOA1
Protein: p.Pro31Ala
Coding: c.91C>G
MANE Select: NM_000039
dbSNP: rs764283540
Type: single nucleotide variant
Location: chr11:116837110 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.66 · 31 PDB
Residue 31: a UniProt-annotated variant site (in fha2; no protein expression)

Full APOA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APOA1 p.Pro31Ser Uncertain significance ★ ⚠ same residue
APOA1 p.Arg197Pro Pathogenic ★★ same type
APOA1 p.Gln23Ter Pathogenic ★★ same type
APOA1 p.Gly50Arg Pathogenic ★★ same type
APOA1 c.-21+22G>A Uncertain significance ★★ same type
APOA1 p.Ala176Thr Uncertain significance ★★ ⚠ same type
APOA1 p.Ala176Val Uncertain significance ★★ ⚠ same type
APOA1 p.Ala204Val 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/apoa1-p-pro31ala (accessed [today's date]).

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