Is GPAA1 p.Arg296Pro (c.887G>C) pathogenic?

GPAA1 p.Arg296Pro (c.887G>C) is classified Uncertain significance in GPAA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-10). AlphaMissense: ambiguous (0.4083); Very rare (popmax 8.48e-05%, nfe).

How common is GPAA1 p.Arg296Pro (c.887G>C) in the general population?

GPAA1 p.Arg296Pro (c.887G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about GPAA1 p.Arg296Pro (c.887G>C)?

AlphaMissense predicts ambiguous (score 0.4083) — an in-silico prediction, not a clinical call.

GPAA1 p.Arg296Pro

c.887G>C · rs782195029 · VCV1490800

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4083 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4083	ambiguous
REVEL	0.434	indeterminate
SaProt	LLR -10.18	damaging
Splicing
SpliceAI	Δ0.52	acceptor gain · deltas
Pangolin	Δ0.34	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6.3	GERP -2.7, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 3,391 bp · p 0.14 · regional, not allelic
Overall
CADD	22.9	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 8.48e-05% European (non-Finnish) · 1/1,179,912 alleles

Overall 6.2e-05% 1/1,613,306 alleles · very rare exomes 1/1,460,970 · genomes 0/152,336 · 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: GPAA1
Protein: p.Arg296Pro
Coding: c.887G>C
MANE Select: NM_003801
dbSNP: rs782195029
Type: single nucleotide variant
Location: chr8:144084486 (GRCh38)
Gene constraint: LOEUF 1.077 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.48 · 4 PDB
Residue 296: an α-helix

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

Similar variants

GPAA1 p.Arg296Trp Uncertain significance ★★ ⚠ same residue
GPAA1 p.Arg296Gln Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg296pro (accessed [today's date]).

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