# NM_033419.5(PGAP3):c.465T>C (p.Val155=)

https://sugi.bio/variant/pgap3-p-val155

## Summary

**PGAP3 p.Val155= (c.465T>C)** is classified **Benign** in PGAP3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-03). Common (popmax 76.9%, sas) — too common for a highly-penetrant pathogenic allele; Associated with hyperphosphatasia with intellectual disability syndrome 4.

**At a glance:** Benign · review: Multiple submitters · rsID rs2941504 · 6 submitters · 1 linked condition · common (popmax 76.9%, sas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the PGAP3 gene that is classified as benign — not considered disease-causing, submitted by 6 submitters, and is linked to hyperphosphatasia with intellectual disability syndrome 4.

*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 | PGAP3 is a diagnostic-grade gene on 12 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/0018352/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PGAP3](https://sugi.bio/atlas/gene/PGAP3/) |
| Protein change (HGVS p.) | p.Val155= |
| Coding change (HGVS c.) | c.465T>C |
| MANE Select transcript | [NM_033419](https://www.ncbi.nlm.nih.gov/nuccore/NM_033419) |
| dbSNP | [rs2941504](https://www.ncbi.nlm.nih.gov/snp/rs2941504/) |
| Variant type | single nucleotide variant |
| Location | chr17:39674647-39674647 (GRCh38) |
| ClinVar | [VCV679984](https://www.ncbi.nlm.nih.gov/clinvar/variation/679984/) |

**All HGVS expressions:** `NC_000017.10:g.37830900A>G`, `NC_000017.11:g.39674647A>G`, `NG_034125.1:g.18424T>C`, `NM_001291726.2:c.312T>C`, `NM_001291728.2:c.433-593T>C`, `NM_001291730.2:c.465T>C`, `NM_001291732.2:c.433-593T>C`, `NM_001291733.2:c.433-1781T>C`, `NM_033419.5:c.465T>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 76.9%, sas) — too common for a highly-penetrant pathogenic allele.

- **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 2.944, GERP -3.81, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 9.921**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for PGAP3 (1,539 scored positions, the nearest 1 base away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **76.9%** (sas) · FAF95 76.4% · FAF99 76.2% · 64,541/83,946 in the highest group · 1,062,933/1,549,746 alleles overall — common (popmax 76.9%, sas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 81.3% | 1 |
| South Asian (grpmax) | 76.9% | 1 |
| Middle Eastern | 76.7% | 1 |
| Finnish (not grpmax-eligible) | 72% | 1 |
| Ashkenazi Jewish (not grpmax-eligible) | 70.7% | 1 |
| European (non-Finnish) | 69.8% | 1 |
| Remaining individuals (not grpmax-eligible) | 67.9% | 1 |
| Admixed American | 60.1% | 2 |
| African / African-American | 54.8% | 2 |
| East Asian | 45.5% | 2 |

Amish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**PGAP3** population constraint: LOEUF 1.147, pLI 9.5295e-10, missense-Z -0.46076; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **hyperphosphatasia with intellectual disability syndrome 4** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 93.17, 88% of residues very-high.

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

*Describes the biological roles of PGAP3 (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:** PGAP3's established molecular role includes hydrolase activity, acting on ester bonds.


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

**Molecular function:** hydrolase activity, acting on ester bonds.

**Biological process:** GPI anchor metabolic process, GPI anchor biosynthetic process.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-03.

**Submitter consensus:** unanimous (6/6 Benign).

**Submission history:** 6 submissions (2017–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-06-14 |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-09-05 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2017-11-20 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-03 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-28 |

## Associated conditions {#conditions}

[hyperphosphatasia with intellectual disability syndrome 4](https://sugi.bio/atlas/disease/hyperphosphatasia-with-intellectual-disability-syndrome-4/).

**Reported phenotype names (ClinVar):** Hyperphosphatasia with intellectual disability syndrome 4, not provided, not specified, GLYCOSYLPHOSPHATIDYLINOSITOL BIOSYNTHESIS DEFECT 10, Hyperphosphatasia with impaired intellectual development syndrome 4, none provided, AllHighlyPenetrant.

## Similar variants {#similar}

Related PGAP3 variant pages (same residue, condition, or type): [PGAP3 c.558-10G>A](/variant/pgap3-c-558-minus-10g-a), [PGAP3 c.694+1G>A](/variant/pgap3-c-694-plus-1g-a), [PGAP3 p.Asp305Gly](/variant/pgap3-p-asp305gly), [PGAP3 p.Gln89Ter](/variant/pgap3-p-gln89ter), [PGAP3 p.Glu37Ter](/variant/pgap3-p-glu37ter), [PGAP3 p.His284Arg](/variant/pgap3-p-his284arg), [PGAP3 p.His284Tyr](/variant/pgap3-p-his284tyr), [PGAP3 p.Pro105Gln](/variant/pgap3-p-pro105gln).

### 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 679984). 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.*