PGAP2

Chr 11AR

post-GPI attachment to proteins 2

Also known as: CWH43-N, FRAG1, HPMRS3, MRT17, MRT21

NCBI Gene: 27315ENSG00000148985UniProt: Q9UHJ9OMIM: 615187

The protein catalyzes fatty acid remodeling of glycosylphosphatidylinositol (GPI) anchors by replacing unsaturated acyl chains with saturated stearoyl chains, which is critical for proper integration of GPI-anchored proteins into lipid rafts. Mutations cause autosomal recessive hyperphosphatasia with impaired intellectual development syndrome 3, characterized by elevated alkaline phosphatase levels and intellectual disability. The gene is highly constrained against loss-of-function variation (pLI 0.93, LOEUF 0.36), indicating that complete loss of protein function is poorly tolerated.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismARLOEUF 0.361 OMIM phenotype
Clinical Summary— PGAP2
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.93). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
37 unique Pathogenic / Likely Pathogenic· 79 VUS of 196 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.36LOEUF
pLI 0.935
Z-score 3.09
OE 0.08 (0.03–0.36)
Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
0.93Z-score
OE missense 0.82 (0.72–0.93)
168 obs / 205.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.08 (0.03–0.36)
0≤0.351.4
Missense OE0.82 (0.72–0.93)
0≤0.61.4
Synonymous OE1.03
0≤1.21.6
LoF obs/exp: 1 / 13.1Missense obs/exp: 168 / 205.7Syn Z: -0.21

ClinVar Variant Classifications

196 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic26
Likely Pathogenic11
VUS79
Likely Benign35
Benign19
Conflicting6
26
Pathogenic
11
Likely Pathogenic
79
VUS
35
Likely Benign
19
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
4
20
0
26
Likely Pathogenic
3
8
0
0
11
VUS
2
67
10
0
79
Likely Benign
1
25
5
4
35
Benign
1
1
17
0
19
Conflicting
—6
Total9105524176

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

PGAP2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 4 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre.
Pronicka E et al.·J Transl Med
2016
Macrocephaly and Digital Anomalies Expand the Phenotypic Spectrum of PGAP2 Variants in Hyperphosphatasia with Impaired Intellectual Development Syndrome 3 (HPMRS3).
Susgun S et al.·Hum Mutat
2024
PGAP2-Related Hyperphosphatasia-Mental Retardation Syndrome: Report of a Novel Patient, Toward a Broadening of Phenotypic Spectrum and Therapeutic Perspectives.
Saracino A et al.·Neuropediatrics
2024Case report
Congenital disorder of glycosylphosphatidylinositol (GPI)-anchor biosynthesis--The phenotype of two patients with novel mutations in the PIGN and PGAP2 genes.
Jezela-Stanek A et al.·Eur J Paediatr Neurol
2016Case report
A Rare Variant in PGAP2 Causes Autosomal Recessive Hyperphosphatasia with Mental Retardation Syndrome, with a Mild Phenotype in Heterozygous Carriers.
Perez Y et al.·Biomed Res Int
2017Case report
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
PGAP2: A comprehensive toolkit for prokaryotic pan-genome analysis based on fine-grained feature networks.
Bu C et al.·Nat Commun
2025Open Access
Correction to "Macrocephaly and Digital Anomalies Expand the Phenotypic Spectrum of PGAP2 Variants in Hyperphosphatasia with Impaired Intellectual Development Syndrome 3 (HPMRS3)".
·Hum Mutat
2025Open Access
Genome-Wide Identification of the AP2/ERF Gene Family and Functional Analysis of PgAP2/ERF187 Under Cold Stress in Panax ginseng C. A. Meyer.
Wang Y et al.·Plants (Basel)
2025Open AccessFunctional
A Treatable Cause of Seizures and Hyperphosphatasia: Patients with PGAP2 and PGAP3 Mutations.
Burgac E et al.·Mol Syndromol
2026Cohort
A case report of PGAP2-related hyperphosphatasia with impaired intellectual development syndrome in a Chinese family and literature review.
Pan Y et al.·Front Pediatr
2024Open AccessReview
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients