Hyperphosphatasia with intellectual disability syndrome 3

Summary

Hyperphosphatasia with intellectual disability syndrome 3 (MONDO:0013628) is a disease caused by PGAP2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: PGAP2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 30

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperphosphatasia with intellectual disability syndrome 3
Mondo ID	MONDO:0013628
OMIM	614207
DOID	DOID:0070435
UMLS	C3280153
MedGen	481783
GARD	0018350
Is cancer (heuristic)	no

Also known as: HPMRS3 · hyperphosphatasia with intellectual disability syndrome 3 · hyperphosphatasia with intellectual disability syndrome type 3 · hyperphosphatasia with mental retardation syndrome 3 · hyperphosphatasia with mental retardation syndrome type 3 · hyperphosphatasia-intellectual disability syndrome caused by mutation in PGAP2 · mental retardation, autosomal recessive 17 · mental retardation, autosomal recessive 21 · PGAP2 hyperphosphatasia-intellectual disability syndrome

Data availability: 30 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › hyperphosphatasia-intellectual disability syndrome › hyperphosphatasia with intellectual disability syndrome 3

Related subtypes (5): hyperphosphatasia with intellectual disability syndrome 1, hyperphosphatasia with intellectual disability syndrome 2, hyperphosphatasia with intellectual disability syndrome 4, hyperphosphatasia with intellectual disability syndrome 5, hyperphosphatasia with intellectual disability syndrome 6

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

30 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 8 likely pathogenic, 6 pathogenic, 3 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4294005	NM_001256236.2(PGAP2):c.-60_-57del	PGAP2	Pathogenic	criteria provided, single submitter
50502	NM_014489.4(PGAP2):c.479A>G (p.Tyr160Cys)	PGAP2	Pathogenic	criteria provided, single submitter
50503	NM_014489.4(PGAP2):c.713G>C (p.Arg238Pro)	PGAP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
50505	NM_014489.4(PGAP2):c.46C>T (p.Arg16Trp)	PGAP2	Pathogenic	no assertion criteria provided
50506	NM_014489.4(PGAP2):c.491C>T (p.Thr164Ile)	PGAP2	Pathogenic	no assertion criteria provided
694699	NM_014489.4(PGAP2):c.2T>G (p.Met1Arg)	PGAP2	Pathogenic	criteria provided, single submitter
827783	NM_014489.4(PGAP2):c.391G>T (p.Glu131Ter)	PGAP2	Pathogenic	criteria provided, single submitter
1678531	NM_014489.4(PGAP2):c.1A>G (p.Met1Val)	PGAP2	Likely pathogenic	criteria provided, single submitter
2692369	NM_014489.4(PGAP2):c.737G>T (p.Arg246Leu)	PGAP2	Likely pathogenic	criteria provided, single submitter
3731331	NM_014489.4(PGAP2):c.642_645del (p.Leu215fs)	PGAP2	Likely pathogenic	criteria provided, single submitter
4849295	NM_014489.4(PGAP2):c.166-1G>C	PGAP2	Likely pathogenic	criteria provided, single submitter
4849327	NM_014489.4(PGAP2):c.737G>A (p.Arg246Gln)	PGAP2	Likely pathogenic	criteria provided, single submitter
633511	NM_014489.4(PGAP2):c.380C>T (p.Ala127Val)	PGAP2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
802653	NM_014489.4(PGAP2):c.449T>C (p.Phe150Ser)	PGAP2	Likely pathogenic	criteria provided, single submitter
827784	NM_014489.4(PGAP2):c.881C>T (p.Thr294Met)	PGAP2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2235024	NM_014489.4(PGAP2):c.146C>T (p.Thr49Ile)	PGAP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
424970	NM_014489.4(PGAP2):c.530A>G (p.Asn177Ser)	PGAP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
424971	NM_014489.4(PGAP2):c.646G>A (p.Gly216Arg)	PGAP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030428	NM_001346397.2(PGAP2):c.10A>G (p.Ile4Val)	PGAP2	Uncertain significance	criteria provided, single submitter
1416302	NM_014489.4(PGAP2):c.770C>T (p.Ser257Leu)	PGAP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1805802	NM_014489.4(PGAP2):c.657C>T (p.Leu219=)	PGAP2	Uncertain significance	criteria provided, single submitter
2410050	NM_014489.4(PGAP2):c.615T>A (p.Asn205Lys)	PGAP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3391397	NM_014489.4(PGAP2):c.670C>G (p.Leu224Val)	PGAP2	Uncertain significance	criteria provided, single submitter
4079542	NM_014489.4(PGAP2):c.524G>C (p.Arg175Pro)	PGAP2	Uncertain significance	criteria provided, single submitter
4279793	NM_014489.4(PGAP2):c.117C>T (p.Leu39=)	PGAP2	Uncertain significance	criteria provided, single submitter
50504	NM_014489.4(PGAP2):c.563T>C (p.Leu188Ser)	PGAP2	Uncertain significance	criteria provided, single submitter
802650	NM_014489.4(PGAP2):c.391dup (p.Glu131fs)	PGAP2	Uncertain significance	criteria provided, single submitter
802651	NM_014489.4(PGAP2):c.392A>G (p.Glu131Gly)	PGAP2	Uncertain significance	criteria provided, single submitter
802652	NM_014489.4(PGAP2):c.395T>G (p.Val132Gly)	PGAP2	Uncertain significance	criteria provided, single submitter
931683	NM_014489.4(PGAP2):c.349-910C>A	PGAP2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PGAP2	Definitive	Autosomal recessive	hyperphosphatasia with intellectual disability syndrome 3	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PGAP2	Orphanet:247262	Hyperphosphatasia-intellectual disability syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PGAP2	HGNC:17893	ENSG00000148985	Q9UHJ9	Acyltransferase PGAP2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PGAP2	Acyltransferase PGAP2	Involved in the fatty acid remodeling steps of GPI-anchor maturation where the unsaturated acyl chain at sn-2 of inositol phosphate is replaced by a saturated stearoyl chain.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PGAP2	Other/Unknown	no		CWH43_N, PGAP2

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
corpus epididymis	1
lower esophagus mucosa	1
skin of abdomen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PGAP2	280	ubiquitous	marker	corpus epididymis, lower esophagus mucosa, skin of abdomen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PGAP2	887

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PGAP2	Q9UHJ9	90.00

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
GPI anchor biosynthetic process	1	495.6×	0.002	PGAP2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PGAP2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PGAP2

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PGAP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.