Is PIGO p.Leu554= (c.1662G>A) pathogenic?

PIGO p.Leu554= (c.1662G>A) is classified Likely benign in PIGO (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-18). Rare (popmax 0.12%, sas); Associated with hyperphosphatasia with intellectual disability syndrome 2.

What condition is associated with PIGO p.Leu554= (c.1662G>A)?

PIGO p.Leu554= (c.1662G>A) is associated with hyperphosphatasia with intellectual disability syndrome 2 (ClinVar).

How common is PIGO p.Leu554= (c.1662G>A) in the general population?

PIGO p.Leu554= (c.1662G>A) is rare (popmax 0.12%, sas) (gnomAD).

PIGO p.Leu554=

Q: How is Hyperphosphatasia-intellectual disability syndrome inherited?

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

c.1662G>A · rs369433160 · VCV385280

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.12%, sas)

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 0.61	GERP -3.4, phastCons 0.14
Overall
CADD	0.609	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.12% South Asian · 109/91,088 alleles

Filtering AF 0.101% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0946%

Overall 0.0125% 201/1,614,210 alleles · rare exomes 189/1,461,894 · genomes 12/152,316 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.12%	836
Middle Eastern	0.099%	1,010
Remaining individualsnot grpmax-eligible	0.0256%	3,907
Admixed American	0.0167%	6,003
European (non-Finnish)	0.00508%	19,668

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.Leu554=
Coding: c.1662G>A
MANE Select: NM_032634
dbSNP: rs369433160
Type: single nucleotide variant
Location: chr9:35092225 (GRCh38)
Gene constraint: LOEUF 0.89 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.57
Residue 554: 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.Leu554del 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
PIGO p.Arg802Ter 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-leu554 (accessed [today's date]).

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