Is PIGA p.Pro44Ser (c.130C>T) pathogenic?

PIGA p.Pro44Ser (c.130C>T) is classified Uncertain significance in PIGA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-18). AlphaMissense: likely pathogenic (0.9956); Absent from gnomAD v4.1; Associated with multiple congenital anomalies-hypotonia-seizures syndrome 2.

What condition is associated with PIGA p.Pro44Ser (c.130C>T)?

PIGA p.Pro44Ser (c.130C>T) is associated with multiple congenital anomalies-hypotonia-seizures syndrome 2 (ClinVar).

How common is PIGA p.Pro44Ser (c.130C>T) in the general population?

PIGA p.Pro44Ser (c.130C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PIGA p.Pro44Ser (c.130C>T)?

AlphaMissense predicts likely pathogenic (score 0.9956) — an in-silico prediction, not a clinical call.

PIGA p.Pro44Ser

c.130C>T · VCV4686665

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9956 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple congenital anomalies-hypotonia-seizures syndrome 2

Computational evidence

Protein change
AlphaMissense	0.9956	likely pathogenic · top 6% in PIGA
REVEL	0.835	moderately pathogenic-leaning
SaProt	LLR -15.93	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.2, phastCons 1
Regional constraint	o/e 0.11	constrained · MANE · 66 bp · p 0.0001 · regional, not allelic
Overall
CADD	27.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PIGA
Protein: p.Pro44Ser
Coding: c.130C>T
MANE Select: NM_002641
Type: single nucleotide variant
Location: chrX:15331801 (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.Pro44= Likely benign ★ 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-pro44ser (accessed [today's date]).

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