Is GPAA1 p.Pro430Ser (c.1288C>T) pathogenic?

GPAA1 p.Pro430Ser (c.1288C>T) is classified Uncertain significance in GPAA1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-24). AlphaMissense: ambiguous (0.3892); Ultra-rare (popmax 0.0737%, eas); Associated with Inborn genetic diseases.

What condition is associated with GPAA1 p.Pro430Ser (c.1288C>T)?

GPAA1 p.Pro430Ser (c.1288C>T) is associated with Inborn genetic diseases (ClinVar).

How common is GPAA1 p.Pro430Ser (c.1288C>T) in the general population?

GPAA1 p.Pro430Ser (c.1288C>T) is ultra-rare (popmax 0.0737%, eas) (gnomAD).

What do computational predictors say about GPAA1 p.Pro430Ser (c.1288C>T)?

AlphaMissense predicts ambiguous (score 0.3892) — an in-silico prediction, not a clinical call.

GPAA1 p.Pro430Ser

c.1288C>T · rs552282153 · VCV1466984

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3892 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0737%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3892	ambiguous
REVEL	0.291	indeterminate
SaProt	LLR -8.05	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 3,391 bp · p 0.14 · regional, not allelic
Overall
CADD	24.0	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 0.0737% East Asian · 33/44,784 alleles

Filtering AF 0.0539% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0471%

Overall 0.00218% 35/1,608,682 alleles · ultra-rare exomes 29/1,456,364 · genomes 6/152,318 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0737%	1,357
Remaining individualsnot grpmax-eligible	0.0016%	62,310
European (non-Finnish)	8.49e-05%	1,178,105

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.Pro430Ser
Coding: c.1288C>T
MANE Select: NM_003801
dbSNP: rs552282153
Type: single nucleotide variant
Location: chr8:144085316 (GRCh38)
Gene constraint: LOEUF 1.077 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.48 · 4 PDB
Residue 430: an α-helix

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.Pro430Leu Uncertain significance ★ 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
GPAA1 p.Ala74Ser 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-pro430ser (accessed [today's date]).

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