# NM_014489.4(PGAP2):c.251del (p.Val84fs)

https://sugi.bio/variant/pgap2-p-val84fs

## Summary

**PGAP2 p.Val84fs (c.251del)** is classified **Pathogenic** in PGAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-05-19). Ultra-rare (popmax 0.0379%, nfe); Associated with hyperphosphatasia with intellectual disability syndrome 1.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0379%, nfe)

## For patients & families {#patients}

This is a change in the PGAP2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to hyperphosphatasia with intellectual disability syndrome 1.

*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 | PGAP2 is a diagnostic-grade gene on 11 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/0018349/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PGAP2](https://sugi.bio/atlas/gene/PGAP2/) |
| Protein change (HGVS p.) | p.Val84fs |
| Coding change (HGVS c.) | c.251del |
| MANE Select transcript | [NM_014489](https://www.ncbi.nlm.nih.gov/nuccore/NM_014489) |
| Variant type | Deletion |
| Location | chr11:3817438-3817438 (GRCh38) |
| ClinVar | [VCV4857450](https://www.ncbi.nlm.nih.gov/clinvar/variation/4857450/) |

**All HGVS expressions:** `NC_000011.10:g.3817438del`, `NC_000011.9:g.3838668del`, `NG_051812.1:g.24715del`, `NM_001145438.3:c.165+6014del`, `NM_001256235.2:c.135-5471del`, `NM_001256236.2:c.251del`, `NM_001256237.2:c.165+6014del`, `NM_001256238.2:c.165+6014del`, `NM_001256239.2:c.165+6014del`, `NM_001256240.2:c.165+6014del`, `NM_001283038.2:c.165+6014del`, `NM_001283039.2:c.-40-6175del`, `NM_001283040.1:c.162-6832del`, `NM_001346397.2:c.318+6014del`, `NM_001346398.2:c.165+6014del`, `NM_001346399.2:c.-38-5471del`, `NM_001346400.2:c.165+6014del`, `NM_001346401.2:c.-38-5471del`, `NM_001346402.2:c.201-5471del`, `NM_001346403.1:c.251del`, `NM_001346404.1:c.165+6014del`, `NM_001346405.1:c.165+6014del`, `NM_014489.4:c.251del`

## 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 0.47, GERP -1.72, phastCons 0.986 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.871, pLI 0.00010679. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 7**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 27.9**. 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 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 **0.0379%** (nfe) · FAF95 0.0349% · FAF99 0.0338% · 447/1,180,030 in the highest group · 491/1,614,052 alleles overall — ultra-rare (popmax 0.0379%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0379% | 2,640 |
| Finnish (not grpmax-eligible) | 0.0375% | 2,668 |
| Remaining individuals (not grpmax-eligible) | 0.0176% | 5,680 |
| African / African-American | 0.00667% | 14,985 |
| Admixed American | 0.00667% | 14,998 |

*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}

**PGAP2** population constraint: LOEUF 0.871, pLI 0.00010679, missense-Z 1.6257. *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 90.00, 73% of residues very-high.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-05-19.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics, University of Leipzig Medical Center | pathogenic | criteria provided, single submitter | clinical testing | 2026-05-19 |

## Associated conditions {#conditions}

[hyperphosphatasia with intellectual disability syndrome 1](https://sugi.bio/atlas/disease/hyperphosphatasia-with-intellectual-disability-syndrome-1/).

**Reported phenotype names (ClinVar):** Hyperphosphatasia with intellectual disability syndrome 1, MABRY SYNDROME, HYPERPHOSPHATASIA WITH IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME 1, GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 2.

## Similar variants {#similar}

Related PGAP2 variant pages (same residue, condition, or type): [PGAP2 p.Val84Ile](/variant/pgap2-p-val84ile), [PGAP2 p.Gly216Arg](/variant/pgap2-p-gly216arg), [PGAP2 c.-60_-57del](/variant/pgap2-c-minus-60-minus-57del), [PGAP2 p.Leu215fs](/variant/pgap2-p-leu215fs), [PGAP2 c.-32-227_-32-225del](/variant/pgap2-c-minus-32-minus-227-minus-32-minus-225del).

### 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 4857450). 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.*