Is GPAA1 p.Arg97Pro (c.290G>C) pathogenic?

GPAA1 p.Arg97Pro (c.290G>C) is classified Uncertain significance in GPAA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-20). AlphaMissense: likely pathogenic (0.7636); Very rare (popmax 0.00246%, nfe).

How common is GPAA1 p.Arg97Pro (c.290G>C) in the general population?

GPAA1 p.Arg97Pro (c.290G>C) is very rare (popmax 0.00246%, nfe) (gnomAD).

What do computational predictors say about GPAA1 p.Arg97Pro (c.290G>C)?

AlphaMissense predicts likely pathogenic (score 0.7636) — an in-silico prediction, not a clinical call.

GPAA1 p.Arg97Pro

c.290G>C · VCV3379842

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7636 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7636	likely pathogenic
REVEL	0.253	benign-leaning
SaProt	LLR -14.23	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	Δ0.60	donor loss at this position · masked 0 · deltas
Constraint at this position
Conservation	phyloP 2.8	GERP -1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 3,391 bp · p 0.14 · regional, not allelic
Overall
CADD	23.5	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 0.00246% European (non-Finnish) · 29/1,179,962 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00192% 31/1,613,538 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00246%	40,688
Remaining individualsnot grpmax-eligible	0.0016%	62,480
African / African-American	0.00134%	74,880

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: GPAA1
Protein: p.Arg97Pro
Coding: c.290G>C
MANE Select: NM_003801
Type: single nucleotide variant
Location: chr8:144083424 (GRCh38)
Gene constraint: LOEUF 1.077 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.48 · 4 PDB
Residue 97: an α-helix

Full GPAA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GPAA1 p.Arg97Trp Uncertain significance ★ ⚠ same residue
GPAA1 c.1165-1C>T Likely pathogenic ★★ same type
GPAA1 c.366+1G>A Likely pathogenic ★★ same type
GPAA1 c.616+1G>T Likely pathogenic ★★ same type
GPAA1 p.Arg215Ter Pathogenic/Likely pathogenic ★★ same type
GPAA1 p.Leu291Pro Likely pathogenic ★★ same type
GPAA1 p.Ser419Ter Pathogenic/Likely pathogenic ★★ same type
GPAA1 c.1164+1A>G 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/gpaa1-p-arg97pro (accessed [today's date]).

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