# NM_024989.4(PGAP1):c.2591C>T (p.Ala864Val)

https://sugi.bio/variant/pgap1-p-ala864val

## Summary

**PGAP1 p.Ala864Val (c.2591C>T)** is classified **Uncertain significance** in PGAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-16). AlphaMissense: likely benign (0.0953); Very rare (popmax 0.000259%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs749798369 · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.000259%, nfe)

## For patients & families {#patients}

This is a change in the PGAP1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Inborn genetic diseases.

*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:** [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.Ala864Val |
| Coding change (HGVS c.) | c.2591C>T |
| MANE Select transcript | [NM_024989](https://www.ncbi.nlm.nih.gov/nuccore/NM_024989) |
| dbSNP | [rs749798369](https://www.ncbi.nlm.nih.gov/snp/rs749798369/) |
| Variant type | single nucleotide variant |
| Location | chr2:196842760-196842760 (GRCh38) |
| ClinVar | [VCV2663550](https://www.ncbi.nlm.nih.gov/clinvar/variation/2663550/) |

**All HGVS expressions:** `NC_000002.11:g.197707484G>A`, `NC_000002.12:g.196842760G>A`, `NG_046780.1:g.89236C>T`, `NM_001321099.2:c.2069C>T`, `NM_001321100.2:c.1424C>T`, `NM_024989.4:c.2591C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0953)
- REVEL 0.04 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.12 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.20) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 1.336, GERP 0.996, phastCons 0.002 — weakly conserved position
- CADD: **PHRED 16.13**. 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.*
- Regional missense constraint: **o/e 0.92** across the covering region of the MANE Select transcript (196,841,237–196,926,616), spanning 85,379 bp. Chi-square p 0.0064. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.20**, acceptor gain **0.00**, donor gain **0.01**. Largest is donor loss, 39 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.01**.
  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.*
- Population frequency (gnomAD v4.1): grpmax **0.000259%** (nfe) · FAF95 6.9e-05% · FAF99 1.9e-05% · 3/1,160,518 in the highest group · 3/1,583,768 alleles overall — very rare (popmax 0.000259%, 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-06-16.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2023–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-04-28 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-06-16 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related PGAP1 variant pages (same residue, condition, or type): [PGAP1 p.Ala298Thr](/variant/pgap1-p-ala298thr), [PGAP1 p.Ala714Val](/variant/pgap1-p-ala714val), [PGAP1 p.Arg803His](/variant/pgap1-p-arg803his), [PGAP1 p.Arg814Cys](/variant/pgap1-p-arg814cys), [PGAP1 p.Asn129Ser](/variant/pgap1-p-asn129ser), [PGAP1 p.Asn363Asp](/variant/pgap1-p-asn363asp), [PGAP1 p.His261Tyr](/variant/pgap1-p-his261tyr), [PGAP1 p.Ile51Met](/variant/pgap1-p-ile51met).

### 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 2663550). 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.*