# NM_024989.4(PGAP1):c.1272G>A (p.Lys424=)

https://sugi.bio/variant/pgap1-p-lys424

## Summary

**PGAP1 p.Lys424= (c.1272G>A)** is classified **Likely pathogenic** in PGAP1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-01-22). Absent from gnomAD v4.1; Associated with intellectual disability, autosomal recessive 42.

**At a glance:** Likely pathogenic · review: No assertion criteria · rsID rs2468647366 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the PGAP1 gene that is considered likely disease-causing, 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.Lys424= |
| Coding change (HGVS c.) | c.1272G>A |
| MANE Select transcript | [NM_024989](https://www.ncbi.nlm.nih.gov/nuccore/NM_024989) |
| dbSNP | [rs2468647366](https://www.ncbi.nlm.nih.gov/snp/rs2468647366/) |
| Variant type | single nucleotide variant |
| Location | chr2:196885424-196885424 (GRCh38) |
| ClinVar | [VCV2687791](https://www.ncbi.nlm.nih.gov/clinvar/variation/2687791/) |

**All HGVS expressions:** `NC_000002.11:g.197750148C>T`, `NC_000002.12:g.196885424C>T`, `NG_046780.1:g.46572G>A`, `NM_001321099.2:c.750G>A`, `NM_001321100.2:c.105G>A`, `NM_024989.4:c.1272G>A`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.95) — consistent with the pathogenic call
- Conservation: phyloP 7.495, GERP 1.83, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 22.8**. 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 deltas (raw): acceptor loss **0.01**, donor loss **0.95**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.78** (loss), gain 0.01 / loss 0.78. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**Likely pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-01-22.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| SC Genetica Medica, ASST Santi Paolo e Carlo | Likely pathogenic | no assertion criteria provided | clinical testing | 2024-01-22 |

## 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.

## Similar variants {#similar}

Related PGAP1 variant pages (same residue, condition, or type): [PGAP1 p.Gln466Ter](/variant/pgap1-p-gln466ter), [PGAP1 p.Gln555Ter](/variant/pgap1-p-gln555ter), [PGAP1 p.Tyr758Ter](/variant/pgap1-p-tyr758ter), [PGAP1 p.Ala298Thr](/variant/pgap1-p-ala298thr), [PGAP1 p.Ala714Val](/variant/pgap1-p-ala714val), [PGAP1 p.Arg231Gln](/variant/pgap1-p-arg231gln), [PGAP1 p.Arg250His](/variant/pgap1-p-arg250his), [PGAP1 p.Arg803Cys](/variant/pgap1-p-arg803cys).

### 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 2687791). 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.*