# NM_024989.4(PGAP1):c.1394_1397del (p.Ile465fs)

https://sugi.bio/variant/pgap1-p-ile465fs

## Summary

**PGAP1 p.Ile465fs (c.1394_1397del)** is classified **Pathogenic** in PGAP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-29). Very rare (popmax 0.00684%, amr); Associated with intellectual disability, autosomal recessive 42.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs781325598 · 3 submitters · 1 linked condition · very rare (popmax 0.00684%, amr)

## For patients & families {#patients}

This is a change in the PGAP1 gene that is considered disease-causing, submitted by 3 submitters, 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.Ile465fs |
| Coding change (HGVS c.) | c.1394_1397del |
| MANE Select transcript | [NM_024989](https://www.ncbi.nlm.nih.gov/nuccore/NM_024989) |
| dbSNP | [rs781325598](https://www.ncbi.nlm.nih.gov/snp/rs781325598/) |
| Variant type | Microsatellite |
| Location | chr2:196875775-196875778 (GRCh38) |
| ClinVar | [VCV474988](https://www.ncbi.nlm.nih.gov/clinvar/variation/474988/) |

**All HGVS expressions:** `NC_000002.11:g.197740500GTAT[1]`, `NC_000002.12:g.196875776GTAT[1]`, `NG_046780.1:g.56214TACA[1]`, `NM_001321099.2:c.872_875del`, `NM_001321100.2:c.227_230del`, `NM_024989.3:c.1394_1397delTACA`, `NM_024989.4:c.1394_1397del`, `NM_024989.4:c.1394_1397delTACA`

## 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 -1.323, GERP -0.701 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- 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 14 of 27**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 29.5**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite 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 **0.00684%** (amr) · FAF95 0.0023% · FAF99 0.00138% · 4/58,472 in the highest group · 6/1,542,214 alleles overall — very rare (popmax 0.00684%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00684% | 14,618 |
| European (non-Finnish) | 0.000179% | 559,488 |

*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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-29.

**Submitter consensus:** unanimous (3/3 Pathogenic).

**Submission history:** 3 submissions (2023–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-02-20 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-29 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-01 |

## 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, not provided, GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 9, Neurodevelopmental disorder with dysmorphic features, spasticity, and brain abnormalities, none provided.

## Similar variants {#similar}

Related PGAP1 variant pages (same residue, condition, or type): [PGAP1 p.Leu197del](/variant/pgap1-p-leu197del), [PGAP1 c.808-7_808-3del](/variant/pgap1-c-808-minus-7-808-minus-3del), [PGAP1 c.1174-20_1174-16del](/variant/pgap1-c-1174-minus-20-1174-minus-16del), [PGAP1 c.861-14_861-11del](/variant/pgap1-c-861-minus-14-861-minus-11del), [PGAP1 p.Arg786fs](/variant/pgap1-p-arg786fs), [PGAP1 p.Gln466Ter](/variant/pgap1-p-gln466ter), [PGAP1 p.Gln555Ter](/variant/pgap1-p-gln555ter), [PGAP1 p.Leu681fs](/variant/pgap1-p-leu681fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 474988). 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.*