PGAP2

Chr 11AR

post-GPI attachment to proteins 2

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

NCBI Gene: 27315ENSG00000148985UniProt: Q9UHJ9

The protein encoded by this gene plays a role in the maturation of glycosylphosphatidylinositol (GPI) anchors on GPI-anchored proteins. Mutations in this gene are associated with an autosomal recessive syndrome characterized by hyperphosphatasia and intellectual disability. [provided by RefSeq, Jul 2017]

Primary Disease Associations & Inheritance

Hyperphosphatasia with impaired intellectual development syndrome 3MIM #614207
AR
0
Active trials
35
Pathogenic / LP
172
ClinVar variants
8
Pubs (1 yr)
0.9
Missense Z
0.36
LOEUF
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
35 Pathogenic / Likely Pathogenic· 78 VUS of 172 total submissions

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

172 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic26
Likely Pathogenic9
VUS78
Likely Benign34
Benign19
Conflicting6
26
Pathogenic
9
Likely Pathogenic
78
VUS
34
Likely Benign
19
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
5
20
0
26
Likely Pathogenic
2
7
0
0
9
VUS
1
67
10
0
78
Likely Benign
0
24
5
5
34
Benign
0
1
17
1
19
Conflicting
—6
Total4104526172

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

View in ClinVar →

PGAP2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

PGAP2-related intellectual disability

definitive
ARLoss Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
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
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
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
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
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
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
2025Cohort
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