Is PIGO p.Ser191Phe (c.572C>T) pathogenic?

PIGO p.Ser191Phe (c.572C>T) is classified Conflicting classifications of pathogenicity in PIGO (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-05). AlphaMissense: likely benign (0.1136); Rare (popmax 0.197%, sas); Associated with hyperphosphatasia with intellectual disability syndrome 2.

What condition is associated with PIGO p.Ser191Phe (c.572C>T)?

PIGO p.Ser191Phe (c.572C>T) is associated with hyperphosphatasia with intellectual disability syndrome 2 (ClinVar).

How common is PIGO p.Ser191Phe (c.572C>T) in the general population?

PIGO p.Ser191Phe (c.572C>T) is rare (popmax 0.197%, sas) (gnomAD).

What do computational predictors say about PIGO p.Ser191Phe (c.572C>T)?

AlphaMissense predicts likely benign (score 0.1136) — an in-silico prediction, not a clinical call.

PIGO p.Ser191Phe

Q: How is Hyperphosphatasia-intellectual disability syndrome inherited?

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

c.572C>T · rs779897930 · VCV653842

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1136 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.197%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperphosphatasia with intellectual disability syndrome 2

Computational evidence

Protein change
AlphaMissense	0.1136	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -9.53	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 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 6,470 bp · p 2e-05 · regional, not allelic
Overall
CADD	21.2	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.197% South Asian · 178/90,390 alleles

Filtering AF 0.173% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.164%

Overall 0.0117% 188/1,607,676 alleles · rare exomes 184/1,455,510 · genomes 4/152,166 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.197%	508
Remaining individualsnot grpmax-eligible	0.00965%	10,362
African / African-American	0.00404%	24,767
European (non-Finnish)	8.49e-05%	1,178,466

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.Ser191Phe
Coding: c.572C>T
MANE Select: NM_032634
dbSNP: rs779897930
Type: single nucleotide variant
Location: chr9:35094299 (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-ser191phe (accessed [today's date]).

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