Is PIGO p.Arg604fs (c.1810dup) pathogenic?

PIGO p.Arg604fs (c.1810dup) is classified Pathogenic/Likely pathogenic in PIGO (ClinVar, Multiple submitters, 13 submitters; last evaluated 2025-11-19). Ultra-rare (popmax 0.04%, nfe); Associated with PIGO-related disorder.

How common is PIGO p.Arg604fs (c.1810dup) in the general population?

PIGO p.Arg604fs (c.1810dup) is ultra-rare (popmax 0.04%, nfe) (gnomAD).

PIGO p.Arg604fs

Q: What condition is associated with PIGO p.Arg604fs (c.1810dup)?

PIGO p.Arg604fs (c.1810dup) is associated with PIGO-related disorder, hyperphosphatasia with intellectual disability syndrome 2, hyperphosphatasia-intellectual disability syndrome (ClinVar).

c.1810dup · rs774508288 · VCV286126

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.04%, nfe)

Conditions

PIGO-related disorder

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 7 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.3	GERP 0.62, phastCons 1
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.04% European (non-Finnish) · 472/1,180,038 alleles

Filtering AF 0.0369% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0358%

Overall 0.0302% 487/1,614,072 alleles · ultra-rare exomes 466/1,461,870 · genomes 21/152,202 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.04%	2,500
Remaining individualsnot grpmax-eligible	0.0176%	5,681
African / African-American	0.004%	24,977
Finnishnot grpmax-eligible	0.00156%	64,020

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.Arg604fs
Coding: c.1810dup
MANE Select: NM_032634
dbSNP: rs774508288
Type: Duplication
Location: chr9:35092076 (GRCh38)
Gene constraint: LOEUF 0.89 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.57
Residue 604: a UniProt-annotated variant site (in hpmrs2)

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

Disease context

PIGO-related disorder

Also linked: hyperphosphatasia with intellectual disability syndrome 2 hyperphosphatasia-intellectual disability syndrome

Similar variants

PIGO p.Arg604Cys Uncertain significance ★★ ⚠ same residue
PIGO p.Arg604His Conflicting classifications of pathogenicity ★ ⚠ same residue
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.Arg69fs Pathogenic ★ same condition
PIGO p.Gly351_Glu352insTer 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-arg604fs (accessed [today's date]).

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