Is GPAA1 p.Pro491Ser (c.1471C>T) pathogenic?

GPAA1 p.Pro491Ser (c.1471C>T) is classified Uncertain significance in GPAA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: likely benign (0.0715); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with GPAA1 p.Pro491Ser (c.1471C>T)?

GPAA1 p.Pro491Ser (c.1471C>T) is associated with Inborn genetic diseases (ClinVar).

How common is GPAA1 p.Pro491Ser (c.1471C>T) in the general population?

GPAA1 p.Pro491Ser (c.1471C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about GPAA1 p.Pro491Ser (c.1471C>T)?

AlphaMissense predicts likely benign (score 0.0715) — an in-silico prediction, not a clinical call.

GPAA1 p.Pro491Ser

c.1471C>T · VCV4621027

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0715 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0715	likely benign
REVEL	0.137	moderately benign-leaning
SaProt	LLR -5.94	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 0.55	GERP -3.5, phastCons 0.019
Regional constraint	o/e 0.95	unconstrained · MANE · 3,391 bp · p 0.14 · regional, not allelic
Overall
CADD	8.932	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 · 1/74,916 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,613,574 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,916
European (non-Finnish)	0.000254%	393,311

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.Pro491Ser
Coding: c.1471C>T
MANE Select: NM_003801
Type: single nucleotide variant
Location: chr8:144085592 (GRCh38)
Gene constraint: LOEUF 1.077 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.48 · 4 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GPAA1 p.Pro491Leu Uncertain significance ★★ ⚠ same residue
GPAA1 p.Pro491= Likely benign ★ same residue
GPAA1 c.254+6C>T Uncertain significance ★★ same condition
GPAA1 p.Ala377Thr Uncertain significance ★★ ⚠ same condition
GPAA1 p.Ala463Val Uncertain significance ★★ same condition
GPAA1 p.Ala570Val Uncertain significance ★★ ⚠ same condition
GPAA1 p.Ala575Ser Uncertain significance ★★ ⚠ same condition
GPAA1 p.Ala597Thr 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/gpaa1-p-pro491ser (accessed [today's date]).

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