# NM_024989.4(PGAP1):c.275del (p.Pro92fs)

https://sugi.bio/variant/pgap1-p-pro92fs

## Summary

**PGAP1 p.Pro92fs (c.275del)** is classified **Pathogenic** in PGAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-27). Very rare (popmax 0.00017%, nfe); Associated with intellectual disability, autosomal recessive 42.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2468726625 · 1 submitter · 1 linked condition · very rare (popmax 0.00017%, nfe)

## For patients & families {#patients}

This is a change in the PGAP1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to intellectual disability, autosomal recessive 42.

*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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0022564/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PGAP1](https://sugi.bio/atlas/gene/PGAP1/) |
| Protein change (HGVS p.) | p.Pro92fs |
| Coding change (HGVS c.) | c.275del |
| MANE Select transcript | [NM_024989](https://www.ncbi.nlm.nih.gov/nuccore/NM_024989) |
| dbSNP | [rs2468726625](https://www.ncbi.nlm.nih.gov/snp/rs2468726625/) |
| Variant type | Deletion |
| Location | chr2:196920023-196920023 (GRCh38) |
| ClinVar | [VCV2023072](https://www.ncbi.nlm.nih.gov/clinvar/variation/2023072/) |

**All HGVS expressions:** `NC_000002.11:g.197784748del`, `NC_000002.12:g.196920024del`, `NG_046780.1:g.11973del`, `NM_001321099.2:c.-248del`, `NM_001321100.2:c.-837del`, `NM_024989.4:c.275del`

## 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 1.059, GERP -0.708, phastCons 0.99 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.691, pLI 0.020573. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 27**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00017%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,178,950 in the highest group · 2/1,611,184 alleles overall — very rare (popmax 0.00017%, 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}

**PGAP1** population constraint: LOEUF 0.691, pLI 0.020573, missense-Z 1.1001. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 89.15, 73% of residues very-high.

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

*Describes the biological roles of PGAP1 (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:** PGAP1's established molecular role includes deacylase activity.


### Pathways affected {#pathways}

PGAP1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Attachment of GPI anchor to uPAR](https://reactome.org/content/detail/R-HSA-162791) | curated |

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

**Molecular function:** deacylase activity.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-11-27.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-11-27 |

## Associated conditions {#conditions}

[intellectual disability, autosomal recessive 42](https://sugi.bio/atlas/disease/intellectual-disability-autosomal-recessive-42/).

**Reported phenotype names (ClinVar):** Intellectual disability, autosomal recessive 42, GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 9, Neurodevelopmental disorder with dysmorphic features, spasticity, and brain abnormalities.

## Same-residue context {#hotspot}

Residue **92** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [PGAP1 p.Pro92del](/variant/pgap1-p-pro92del). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PGAP1 variant pages (same residue, condition, or type): [PGAP1 p.Pro92del](/variant/pgap1-p-pro92del), [PGAP1 p.Leu681fs](/variant/pgap1-p-leu681fs), [PGAP1 c.1426+1del](/variant/pgap1-c-1426-plus-1del), [PGAP1 p.Asn7fs](/variant/pgap1-p-asn7fs), [PGAP1 p.Cys623fs](/variant/pgap1-p-cys623fs), [PGAP1 p.Lys308fs](/variant/pgap1-p-lys308fs), [PGAP1 p.Ser97fs](/variant/pgap1-p-ser97fs), [PGAP1 p.Val516fs](/variant/pgap1-p-val516fs).

### 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 2023072). 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.*