Is PIGO p.Arg445Pro (c.1334G>C) pathogenic?

PIGO p.Arg445Pro (c.1334G>C) is classified Likely pathogenic in PIGO (ClinVar, Single submitter, 1 submitter; last evaluated 2026-07-20). AlphaMissense: likely pathogenic (0.7296); Very rare (popmax 0.00133%, afr); Associated with hyperphosphatasia with intellectual disability syndrome 2.

What condition is associated with PIGO p.Arg445Pro (c.1334G>C)?

PIGO p.Arg445Pro (c.1334G>C) is associated with hyperphosphatasia with intellectual disability syndrome 2 (ClinVar).

How common is PIGO p.Arg445Pro (c.1334G>C) in the general population?

PIGO p.Arg445Pro (c.1334G>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about PIGO p.Arg445Pro (c.1334G>C)?

AlphaMissense predicts likely pathogenic (score 0.7296) — an in-silico prediction, not a clinical call.

PIGO p.Arg445Pro

Q: How is Hyperphosphatasia-intellectual disability syndrome inherited?

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

c.1334G>C · VCV4879964

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7296 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hyperphosphatasia with intellectual disability syndrome 2

Computational evidence

Protein change
AlphaMissense	0.7296	likely pathogenic ✓ concordant with ClinVar
REVEL	0.434	indeterminate
SaProt	LLR -11.19	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.45	GERP 0.63, phastCons 0.19
Regional constraint	o/e 0.88	unconstrained · MANE · 6,470 bp · p 2e-05 · regional, not allelic
Overall
CADD	22.8	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 0.00133% African / African-American · 1/75,062 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,614,214 alleles · very rare exomes 3/1,461,860 · genomes 0/152,354 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,062
European (non-Finnish)	0.000169%	590,012

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: PIGO
Protein: p.Arg445Pro
Coding: c.1334G>C
MANE Select: NM_032634
Type: single nucleotide variant
Location: chr9:35092553 (GRCh38)
Gene constraint: LOEUF 0.89 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.57
Residue 445: 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 p.Arg445Cys Uncertain significance ★★ ⚠ same residue
PIGO p.Arg445His Uncertain significance ★★ ⚠ same residue
PIGO p.Arg445= Likely benign ★ same residue
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

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-arg445pro (accessed [today's date]).

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