Is PIGO p.Arg69fs (c.204dup) pathogenic?

PIGO p.Arg69fs (c.204dup) is classified Pathogenic in PIGO (ClinVar, Single submitter, 1 submitter; last evaluated 2018-09-18). Very rare (popmax 0.000169%, nfe); Associated with hyperphosphatasia with intellectual disability syndrome 2.

What condition is associated with PIGO p.Arg69fs (c.204dup)?

PIGO p.Arg69fs (c.204dup) is associated with hyperphosphatasia with intellectual disability syndrome 2 (ClinVar).

How common is PIGO p.Arg69fs (c.204dup) in the general population?

PIGO p.Arg69fs (c.204dup) is very rare (popmax 0.000169%, nfe) (gnomAD).

PIGO p.Arg69fs

Q: How is Hyperphosphatasia-intellectual disability syndrome inherited?

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

c.204dup · rs751086453 · VCV574401

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

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 2 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.6	GERP -2.2, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,026 alleles

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

Overall 0.000124% 2/1,614,130 alleles · very rare exomes 2/1,461,872 · genomes 0/152,258 · joint denominator

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.Arg69fs
Coding: c.204dup
MANE Select: NM_032634
dbSNP: rs751086453
Type: Duplication
Location: chr9:35095361 (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.Arg69Gln Uncertain significance ★ ⚠ same residue
PIGO p.Arg604fs Pathogenic/Likely pathogenic ★★ same condition
PIGO p.Arg731fs Pathogenic/Likely pathogenic ★★ same condition
PIGO p.Thr788fs Pathogenic/Likely pathogenic ★★ same condition
PIGO p.Ala149fs Pathogenic ★ same condition
PIGO p.Arg615fs Pathogenic ★ same condition
PIGO p.Gly351_Glu352insTer Pathogenic ★ same condition
PIGO p.Gly46fs 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-arg69fs (accessed [today's date]).

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