Is PIGO p.Ser447Pro (c.1339T>C) pathogenic?

PIGO p.Ser447Pro (c.1339T>C) is classified Uncertain significance in PIGO (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-10). AlphaMissense: ambiguous (0.5509); Absent from gnomAD v4.1; Associated with hyperphosphatasia with intellectual disability syndrome 2.

What condition is associated with PIGO p.Ser447Pro (c.1339T>C)?

PIGO p.Ser447Pro (c.1339T>C) is associated with hyperphosphatasia with intellectual disability syndrome 2 (ClinVar).

How common is PIGO p.Ser447Pro (c.1339T>C) in the general population?

PIGO p.Ser447Pro (c.1339T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PIGO p.Ser447Pro (c.1339T>C)?

AlphaMissense predicts ambiguous (score 0.5509) — an in-silico prediction, not a clinical call.

PIGO p.Ser447Pro

Q: How is Hyperphosphatasia-intellectual disability syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1339T>C · VCV3699874

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5509 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

hyperphosphatasia with intellectual disability syndrome 2

Computational evidence

Protein change
AlphaMissense	0.5509	ambiguous
REVEL	0.249	benign-leaning
SaProt	LLR -11.11	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 6,470 bp · p 2e-05 · regional, not allelic
Overall
CADD	23.9	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

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: PIGO
Protein: p.Ser447Pro
Coding: c.1339T>C
MANE Select: NM_032634
Type: single nucleotide variant
Location: chr9:35092548 (GRCh38)
Gene constraint: LOEUF 0.89 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.57
Residue 447: a UniProt-annotated variant site (in hpmrs2)

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

Disease context

hyperphosphatasia with intellectual disability syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hyperphosphatasia-intellectual disability syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

PIGO c.2648-1G>A Likely pathogenic ★★ same condition
PIGO c.3069+2T>C Likely pathogenic ★★ same condition
PIGO c.3069+5G>A Pathogenic/Likely pathogenic ★★ same condition
PIGO p.Arg119Trp Likely pathogenic ★★ ⚠ same condition
PIGO p.Arg122Ter Pathogenic/Likely pathogenic ★★ same condition
PIGO p.Arg376Ter Pathogenic/Likely pathogenic ★★ same condition
PIGO p.Arg802Ter Pathogenic/Likely pathogenic ★★ same condition
PIGO p.Gln372Ter Pathogenic ★★ 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/pigo-p-ser447pro (accessed [today's date]).

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