Is PIGA p.Pro422= (c.1266A>G) pathogenic?

PIGA p.Pro422= (c.1266A>G) is classified Uncertain significance in PIGA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). Absent from gnomAD v4.1; Associated with multiple congenital anomalies-hypotonia-seizures syndrome 2.

What condition is associated with PIGA p.Pro422= (c.1266A>G)?

PIGA p.Pro422= (c.1266A>G) is associated with multiple congenital anomalies-hypotonia-seizures syndrome 2 (ClinVar).

How common is PIGA p.Pro422= (c.1266A>G) in the general population?

PIGA p.Pro422= (c.1266A>G) is absent from gnomAD v4.1 (gnomAD).

PIGA p.Pro422=

c.1266A>G · VCV4717326

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

multiple congenital anomalies-hypotonia-seizures syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.63	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP -2.7	GERP -4
Overall
CADD	3.305	PHRED · no single calibrated threshold — expert panels disagree

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.Pro422=
Coding: c.1266A>G
MANE Select: NM_002641
Type: single nucleotide variant
Location: chrX:15321695 (GRCh38)
Structure: AlphaFold pLDDT 86.22
Residue 422: a UniProt-annotated variant site (in mcahs2; decreased function in gpi anchor biosynthesis; does not fully restore gpi-anchored cd59 surface expression when transfected in piga-null cells; does not rescue defective hamp expression in piga-deficient cells overexpressing hjv, suggesting absent or reduced hjv anchorage at the cell membrane)

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.Pro422Ala Uncertain significance ★ ⚠ 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-pro422 (accessed [today's date]).

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