# NM_032634.4(PIGO):c.246C>T (p.Phe82=)

https://sugi.bio/variant/pigo-p-phe82

## Summary

**PIGO p.Phe82= (c.246C>T)** is classified **Likely benign** in PIGO (ClinVar, Single submitter, 2 submitters; last evaluated 2023-05-12). Very rare (popmax 0.000678%, nfe); Associated with hyperphosphatasia with intellectual disability syndrome 2.

**At a glance:** Likely benign · review: Single submitter · rsID rs748671184 · 2 submitters · 1 linked condition · very rare (popmax 0.000678%, nfe)

## For patients & families {#patients}

This is a change in the PIGO gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to hyperphosphatasia with intellectual disability syndrome 2.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Diagnostic panels | PIGO is a diagnostic-grade gene on 12 Genomics England panels |

**Commonly reported features of Hyperphosphatasia-intellectual disability syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypertelorism — Very frequent (99-80%)
- Seizure — Very frequent (99-80%)
- Global developmental delay — Very frequent (99-80%)
- Elevated circulating alkaline phosphatase concentration — Very frequent (99-80%)
- Shortening of all distal phalanges of the fingers — Very frequent (99-80%)
- Floppy infant — Very frequent (99-80%)
- Wide nasal bridge — Frequent (79-30%)
- Long palpebral fissure — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018351/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PIGO](https://sugi.bio/atlas/gene/PIGO/) |
| Protein change (HGVS p.) | p.Phe82= |
| Coding change (HGVS c.) | c.246C>T |
| MANE Select transcript | [NM_032634](https://www.ncbi.nlm.nih.gov/nuccore/NM_032634) |
| dbSNP | [rs748671184](https://www.ncbi.nlm.nih.gov/snp/rs748671184/) |
| Variant type | single nucleotide variant |
| Location | chr9:35095320-35095320 (GRCh38) |
| ClinVar | [VCV1096416](https://www.ncbi.nlm.nih.gov/clinvar/variation/1096416/) |

**All HGVS expressions:** `NC_000009.11:g.35095317G>A`, `NC_000009.12:g.35095320G>A`, `NG_031990.1:g.6282C>T`, `NM_001201484.2:c.246C>T`, `NM_032634.3:c.246C>T`, `NM_032634.4:c.246C>T`, `NM_152850.4:c.246C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.346, GERP -2.88, phastCons 0.629 — weakly conserved position
- CADD: **PHRED 12.95**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.22 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000678%** (nfe) · FAF95 0.000292% · FAF99 0.000211% · 8/1,180,018 in the highest group · 8/1,614,176 alleles overall — very rare (popmax 0.000678%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**PIGO** population constraint: LOEUF 0.89, pLI 1.7784e-16, missense-Z 2.1062. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **complex neurodevelopmental disorder** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 82.57, 47% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of PIGO (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** PIGO's established molecular role includes mannose-ethanolamine phosphotransferase activity.


### Pathways affected {#pathways}

PIGO participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Synthesis of glycosylphosphatidylinositol (GPI)](https://reactome.org/content/detail/R-HSA-162710) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** mannose-ethanolamine phosphotransferase activity.

**Biological process:** GPI anchor biosynthetic process.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-05-12.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2019–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-06-21 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-05-12 |

## Associated conditions {#conditions}

[hyperphosphatasia with intellectual disability syndrome 2](https://sugi.bio/atlas/disease/hyperphosphatasia-with-intellectual-disability-syndrome-2/).

**Reported phenotype names (ClinVar):** Hyperphosphatasia with intellectual disability syndrome 2, PIGO-related disorder, GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 6, HYPERPHOSPHATASIA WITH IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME 2, PIGO-related condition.

## Similar variants {#similar}

Related PIGO variant pages (same residue, condition, or type): [PIGO p.Phe82Val](/variant/pigo-p-phe82val), [PIGO c.2648-1G>A](/variant/pigo-c-2648-minus-1g-a), [PIGO c.3069+2T>C](/variant/pigo-c-3069-plus-2t-c), [PIGO c.3069+5G>A](/variant/pigo-c-3069-plus-5g-a), [PIGO p.Arg119Trp](/variant/pigo-p-arg119trp), [PIGO p.Arg122Ter](/variant/pigo-p-arg122ter), [PIGO p.Arg376Ter](/variant/pigo-p-arg376ter), [PIGO p.Arg802Ter](/variant/pigo-p-arg802ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1096416). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*