Is PIGA p.Ala15Pro (c.43G>C) pathogenic?

PIGA p.Ala15Pro (c.43G>C) is classified Uncertain significance in PIGA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-03). AlphaMissense: likely benign (0.0755); Very rare (popmax 0.00296%, eas); Associated with multiple congenital anomalies-hypotonia-seizures syndrome 2.

What condition is associated with PIGA p.Ala15Pro (c.43G>C)?

PIGA p.Ala15Pro (c.43G>C) is associated with multiple congenital anomalies-hypotonia-seizures syndrome 2 (ClinVar).

How common is PIGA p.Ala15Pro (c.43G>C) in the general population?

PIGA p.Ala15Pro (c.43G>C) is very rare (popmax 0.00296%, eas) (gnomAD).

What do computational predictors say about PIGA p.Ala15Pro (c.43G>C)?

AlphaMissense predicts likely benign (score 0.0755) — an in-silico prediction, not a clinical call.

PIGA p.Ala15Pro

c.43G>C · rs369608621 · VCV1005912

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0755 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00296%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple congenital anomalies-hypotonia-seizures syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0755	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -6.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.36	GERP -2
Regional constraint	o/e 1.03	unconstrained · MANE · 96 bp · p 0.87 · regional, not allelic
Overall
CADD	1.03	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 0.00296% East Asian · 1/33,822 alleles

Overall 8.27e-05% 1/1,208,986 alleles · very rare exomes 1/1,095,530 · genomes 0/113,456 · 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: PIGA
Protein: p.Ala15Pro
Coding: c.43G>C
MANE Select: NM_002641
dbSNP: rs369608621
Type: single nucleotide variant
Location: chrX:15331888 (GRCh38)
Structure: AlphaFold pLDDT 86.22

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

Disease context

multiple congenital anomalies-hypotonia-seizures syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PIGA p.Ala15Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
PIGA p.Arg119Gln Pathogenic/Likely pathogenic ★★ same condition
PIGA p.Arg119Trp Pathogenic/Likely pathogenic ★★ same condition
PIGA p.Arg412Ter Pathogenic ★★ same condition
PIGA p.Arg81His Likely pathogenic ★★ same condition
PIGA p.Val329Ala Likely pathogenic ★★ same condition
PIGA p.Val49Met Pathogenic/Likely pathogenic ★★ same condition
PIGA c.982-3A>C 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/piga-p-ala15pro (accessed [today's date]).

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