Is PIGO p.Val586= (c.1758C>T) pathogenic?

PIGO p.Val586= (c.1758C>T) is classified Conflicting classifications of pathogenicity in PIGO (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-26). Ultra-rare (popmax 0.0657%, mid); Associated with hyperphosphatasia with intellectual disability syndrome 2.

What condition is associated with PIGO p.Val586= (c.1758C>T)?

PIGO p.Val586= (c.1758C>T) is associated with hyperphosphatasia with intellectual disability syndrome 2 (ClinVar).

How common is PIGO p.Val586= (c.1758C>T) in the general population?

PIGO p.Val586= (c.1758C>T) is ultra-rare (popmax 0.0657%, mid) (gnomAD).

PIGO p.Val586=

Q: How is Hyperphosphatasia-intellectual disability syndrome inherited?

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

c.1758C>T · rs144103228 · VCV473217

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0657%, mid)

Conditions

hyperphosphatasia with intellectual disability syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.91	GERP -0.53, phastCons 1
Overall
CADD	2.104	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0657% Middle Eastern · 4/6,084 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0338%

Overall 0.0304% 491/1,614,114 alleles · ultra-rare exomes 456/1,461,890 · genomes 35/152,224 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0657%	1,521
European (non-Finnish)	0.038%	2,634
Remaining individualsnot grpmax-eligible	0.0256%	3,906
Admixed American	0.0167%	6,000
Finnishnot grpmax-eligible	0.00781%	12,806
African / African-American	0.00667%	14,988
South Asian	0.00329%	30,364

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.Val586=
Coding: c.1758C>T
MANE Select: NM_032634
dbSNP: rs144103228
Type: single nucleotide variant
Location: chr9:35092129 (GRCh38)
Gene constraint: LOEUF 0.89 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.57
Residue 586: 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-val586 (accessed [today's date]).

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