Is PIGO p.Ala756= (c.2268G>A) pathogenic?

PIGO p.Ala756= (c.2268G>A) is classified Conflicting classifications of pathogenicity in PIGO (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-05-01). Rare (popmax 0.584%, nfe); Associated with hyperphosphatasia with intellectual disability syndrome 2.

What condition is associated with PIGO p.Ala756= (c.2268G>A)?

PIGO p.Ala756= (c.2268G>A) is associated with hyperphosphatasia with intellectual disability syndrome 2 (ClinVar).

How common is PIGO p.Ala756= (c.2268G>A) in the general population?

PIGO p.Ala756= (c.2268G>A) is rare (popmax 0.584%, nfe) (gnomAD).

PIGO p.Ala756=

Q: How is Hyperphosphatasia-intellectual disability syndrome inherited?

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

c.2268G>A · rs149171782 · VCV198602

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.584%, 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.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.07	GERP 1.5, phastCons 0.064
Overall
CADD	5.387	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.584% European (non-Finnish) · 6,891/1,180,020 alleles

Filtering AF 0.572% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.568%

Overall 0.461% 7,431/1,613,526 alleles · rare exomes 6,975/1,461,256 · genomes 456/152,270 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.584%	171
Remaining individualsnot grpmax-eligible	0.451%	222
Admixed American	0.247%	406
Middle Eastern	0.132%	758
African / African-American	0.08%	1,251
Finnishnot grpmax-eligible	0.0268%	3,730
South Asian	0.0253%	3,960
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
East Asian	0.00223%	44,880

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.Ala756=
Coding: c.2268G>A
MANE Select: NM_032634
dbSNP: rs149171782
Type: single nucleotide variant
Location: chr9:35091619 (GRCh38)
Gene constraint: LOEUF 0.89 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.57
Residue 756: 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.Ala756Val Uncertain significance ★★ ⚠ same residue
PIGO p.Ala756Ser Uncertain significance ★ ⚠ 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
PIGO p.Arg376Ter 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-ala756 (accessed [today's date]).

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