Is PIGO p.Pro197fs (c.589_590del) pathogenic?

PIGO p.Pro197fs (c.589590del) is classified Pathogenic/Likely pathogenic in PIGO (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-09). Very rare (popmax 0.00174%, amr); Associated with hyperphosphatasia with intellectual disability syndrome 2.

What condition is associated with PIGO p.Pro197fs (c.589_590del)?

PIGO p.Pro197fs (c.589_590del) is associated with hyperphosphatasia with intellectual disability syndrome 2 (ClinVar).

How common is PIGO p.Pro197fs (c.589_590del) in the general population?

PIGO p.Pro197fs (c.589_590del) is very rare (popmax 0.00174%, amr) (gnomAD).

PIGO p.Pro197fs

Q: How is Hyperphosphatasia-intellectual disability syndrome inherited?

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

c.589_590del · rs763591247 · VCV632540

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00174%, amr)

Conditions

hyperphosphatasia with intellectual disability syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.1	GERP -3, phastCons 0.73

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00174% Admixed American · 1/57,500 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000343% 5/1,455,984 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00174%	57,500
European (non-Finnish)	0.000339%	294,638

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.Pro197fs
Coding: c.589_590del
MANE Select: NM_032634
dbSNP: rs763591247
Type: Deletion
Location: chr9:35094281 (GRCh38)
Gene constraint: LOEUF 0.89 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.57

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.Pro197Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
PIGO p.Pro197= Likely benign ★ same residue
PIGO p.Ala517fs Pathogenic/Likely pathogenic ★★ same condition
PIGO c.2854+8del Benign/Likely benign ★★ same condition
PIGO p.Ala60fs Pathogenic ★ same condition
PIGO p.Arg450fs Pathogenic ★ same condition
PIGO p.Arg814fs Pathogenic ★ same condition
PIGO p.Cys648fs 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-pro197fs (accessed [today's date]).

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