Is PIGO p.Ser358Phe (c.1073C>T) pathogenic?

PIGO p.Ser358Phe (c.1073C>T) is classified Uncertain significance in PIGO (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-31). AlphaMissense: likely benign (0.0817); Very rare (popmax 8.48e-05%, nfe); Associated with hyperphosphatasia with intellectual disability syndrome 2.

What condition is associated with PIGO p.Ser358Phe (c.1073C>T)?

PIGO p.Ser358Phe (c.1073C>T) is associated with hyperphosphatasia with intellectual disability syndrome 2 (ClinVar).

How common is PIGO p.Ser358Phe (c.1073C>T) in the general population?

PIGO p.Ser358Phe (c.1073C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about PIGO p.Ser358Phe (c.1073C>T)?

AlphaMissense predicts likely benign (score 0.0817) — an in-silico prediction, not a clinical call.

PIGO p.Ser358Phe

Q: How is Hyperphosphatasia-intellectual disability syndrome inherited?

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

c.1073C>T · rs376445701 · VCV944513

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0817 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperphosphatasia with intellectual disability syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0817	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -5.98	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -0.43, phastCons 0.86
Regional constraint	o/e 0.88	unconstrained · MANE · 6,470 bp · p 2e-05 · regional, not allelic
Overall
CADD	18.56	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,900 alleles

Overall 0.000682% 11/1,614,058 alleles · very rare exomes 11/1,461,692 · genomes 0/152,366 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.016%	6,251
European (non-Finnish)grpmax	8.48e-05%	1,179,901

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser358Phe
Coding: c.1073C>T
MANE Select: NM_032634
dbSNP: rs376445701
Type: single nucleotide variant
Location: chr9:35093076 (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 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-ser358phe (accessed [today's date]).

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