Hyperphosphatasia with intellectual disability syndrome 4

Summary

Hyperphosphatasia with intellectual disability syndrome 4 (MONDO:0014318) is a disease caused by PGAP3 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: PGAP3 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 45

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperphosphatasia with intellectual disability syndrome 4
Mondo ID	MONDO:0014318
OMIM	615716
DOID	DOID:0070436
UMLS	C3810354
MedGen	816684
GARD	0018352
Is cancer (heuristic)	no

Also known as: HPMRS4 · hyperphosphatasia with intellectual disability syndrome 4 · hyperphosphatasia with intellectual disability syndrome type 4 · hyperphosphatasia with mental retardation syndrome 4 · hyperphosphatasia with mental retardation syndrome type 4 · hyperphosphatasia-intellectual disability syndrome caused by mutation in PGAP3 · PGAP3 hyperphosphatasia-intellectual disability syndrome

Data availability: 45 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 4

Related subtypes (5): hyperphosphatasia with intellectual disability syndrome 1, hyperphosphatasia with intellectual disability syndrome 3, hyperphosphatasia with intellectual disability syndrome 2, 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

45 retrieved; paginated sample, class counts are floors:

19 pathogenic, 7 likely pathogenic, 6 uncertain significance, 6 pathogenic/likely pathogenic, 5 conflicting classifications of pathogenicity, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
125437	NM_033419.5(PGAP3):c.275G>A (p.Gly92Asp)	PGAP3	Pathogenic	no assertion criteria provided
125439	NM_033419.5(PGAP3):c.914A>G (p.Asp305Gly)	PGAP3	Pathogenic	criteria provided, multiple submitters, no conflicts
125440	NM_033419.5(PGAP3):c.314C>G (p.Pro105Arg)	PGAP3	Pathogenic	no assertion criteria provided
1323441	NM_033419.5(PGAP3):c.455G>A (p.Trp152Ter)	PGAP3	Pathogenic	criteria provided, single submitter
1687230	NM_033419.5(PGAP3):c.452dup (p.Trp152fs)	PGAP3	Pathogenic	criteria provided, multiple submitters, no conflicts
224640	NM_033419.5(PGAP3):c.402dup (p.Met135fs)	PGAP3	Pathogenic	criteria provided, multiple submitters, no conflicts
224641	NM_033419.5(PGAP3):c.861G>T (p.Trp287Cys)	PGAP3	Pathogenic	no assertion criteria provided
224643	NM_033419.5(PGAP3):c.320C>T (p.Ser107Leu)	PGAP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224644	NM_033419.5(PGAP3):c.845A>G (p.Asp282Gly)	PGAP3	Pathogenic	criteria provided, single submitter
224645	NM_033419.5(PGAP3):c.558-10G>A	PGAP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224646	NM_033419.5(PGAP3):c.439dup (p.Leu147fs)	PGAP3	Pathogenic	no assertion criteria provided
224647	NM_033419.5(PGAP3):c.511T>C (p.Cys171Arg)	PGAP3	Pathogenic	no assertion criteria provided
224648	NM_033419.5(PGAP3):c.842T>C (p.Leu281Pro)	PGAP3	Pathogenic	no assertion criteria provided
3028899	NM_033419.5(PGAP3):c.265C>T (p.Gln89Ter)	PGAP3	Pathogenic	criteria provided, multiple submitters, no conflicts
3385330	NM_033419.5(PGAP3):c.355del (p.Leu119fs)	PGAP3	Pathogenic	criteria provided, single submitter
373293	NM_033419.5(PGAP3):c.694+1G>A	PGAP3	Pathogenic	criteria provided, multiple submitters, no conflicts
3775700	NM_033419.5(PGAP3):c.80dup (p.Val28fs)	PGAP3	Pathogenic	criteria provided, single submitter
426134	NM_033419.5(PGAP3):c.827C>T (p.Pro276Leu)	PGAP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
496676	NM_033419.5(PGAP3):c.280del (p.Trp94fs)	PGAP3	Pathogenic	criteria provided, single submitter
520887	NM_033419.5(PGAP3):c.109G>T (p.Glu37Ter)	PGAP3	Pathogenic	criteria provided, multiple submitters, no conflicts
522596	NM_033419.5(PGAP3):c.507C>A (p.Tyr169Ter)	PGAP3	Pathogenic/Likely pathogenic	no assertion criteria provided
522978	NM_033419.5(PGAP3):c.432+1G>A	PGAP3	Pathogenic	criteria provided, single submitter
599004	NM_033419.5(PGAP3):c.851A>G (p.His284Arg)	PGAP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
800935	NM_033419.5(PGAP3):c.850C>T (p.His284Tyr)	PGAP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
982399	NM_033419.5(PGAP3):c.75_81dup (p.Val28Ter)	PGAP3	Pathogenic	no assertion criteria provided
1683736	NM_033419.5(PGAP3):c.50_52delinsC (p.Leu17fs)	PGAP3	Likely pathogenic	criteria provided, single submitter
1705418	NM_033419.5(PGAP3):c.314C>A (p.Pro105Gln)	PGAP3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1802697	NM_033419.5(PGAP3):c.896dup (p.Ser300fs)	PGAP3	Likely pathogenic	criteria provided, single submitter
3362648	NM_033419.5(PGAP3):c.181+1G>T	PGAP3	Likely pathogenic	criteria provided, single submitter
3777111	NM_033419.5(PGAP3):c.900-1G>A	PGAP3	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 4 · 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
PGAP3	Definitive	Autosomal recessive	hyperphosphatasia with intellectual disability syndrome 4	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PGAP3	Orphanet:247262	Hyperphosphatasia-intellectual disability syndrome
LMAN2L	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
SETD5	Orphanet:435638	3p25.3 microdeletion syndrome
SETD5	Orphanet:528084	Non-specific syndromic intellectual disability

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PGAP3	HGNC:23719	ENSG00000161395	Q96FM1	GPI-specific phospholipase A2-like PGAP3	gencc,clinvar
LMAN2L	HGNC:19263	ENSG00000114988	Q9H0V9	VIP36-like protein	clinvar
SETD5	HGNC:25566	ENSG00000168137	Q9C0A6	Histone-lysine N-methyltransferase SETD5	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PGAP3	GPI-specific phospholipase A2-like PGAP3	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.
LMAN2L	VIP36-like protein	May be involved in the regulation of export from the endoplasmic reticulum of a subset of glycoproteins.
SETD5	Histone-lysine N-methyltransferase SETD5	Chromatin regulator required for brain development: acts as a regulator of RNA elongation rate, thereby regulating neural stem cell (NSC) proliferation and synaptic transmission.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PGAP3	Other/Unknown	no		Per1-like
LMAN2L	Other/Unknown	no		Lectin_leg, ConA-like_dom_sf, Intracellular_Lectin-GPT
SETD5	Other/Unknown	no		SET_dom, SETD5_SET, SET_dom_sf

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left lobe of thyroid gland	1
pancreatic ductal cell	1
right lobe of thyroid gland	1
islet of Langerhans	1
ovary	1
renal medulla	1
adrenal tissue	1
colonic epithelium	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PGAP3	270	ubiquitous	marker	pancreatic ductal cell, left lobe of thyroid gland, right lobe of thyroid gland
LMAN2L	267	ubiquitous	marker	islet of Langerhans, renal medulla, ovary
SETD5	284	ubiquitous	marker	adrenal tissue, colonic epithelium, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SETD5	1,865
LMAN2L	1,486
PGAP3	750

Structural data

PDB: 0 · AlphaFold-only: 3 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PGAP3	Q96FM1	93.17
LMAN2L	Q9H0V9	84.90
SETD5	Q9C0A6	47.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 3 evidence-associated genes (1 with Reactome annotation).

Pathways 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.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Cargo concentration in the ER	1	335.9×	0.022	LMAN2L
COPII-mediated vesicle transport	1	163.1×	0.022	LMAN2L
ER to Golgi Anterograde Transport	1	132.8×	0.022	LMAN2L
Transport to the Golgi and subsequent modification	1	102.9×	0.022	LMAN2L
Asparagine N-linked glycosylation	1	60.1×	0.030	LMAN2L
Membrane Trafficking	1	37.1×	0.037	LMAN2L
Vesicle-mediated transport	1	34.8×	0.037	LMAN2L
Post-translational protein modification	1	19.2×	0.059	LMAN2L
Metabolism of proteins	1	12.4×	0.081	LMAN2L

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 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 metabolic process	1	1872.4×	0.004	PGAP3
negative regulation of transcription by RNA polymerase III	1	1123.5×	0.004	SETD5
regulation of DNA-templated transcription elongation	1	936.2×	0.004	SETD5
regulation of chromatin organization	1	510.7×	0.006	SETD5
regulation of synapse assembly	1	234.1×	0.010	SETD5
GPI anchor biosynthetic process	1	165.2×	0.012	PGAP3
cognition	1	95.2×	0.018	SETD5
methylation	1	56.7×	0.026	SETD5
endoplasmic reticulum to Golgi vesicle-mediated transport	1	45.3×	0.029	LMAN2L
protein folding	1	34.5×	0.034	LMAN2L
protein transport	1	14.6×	0.073	LMAN2L
regulation of DNA-templated transcription	1	10.5×	0.092	SETD5

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
PGAP3	0	0
LMAN2L	0	0
SETD5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	PGAP3, LMAN2L, SETD5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PGAP3	0	—
LMAN2L	0	—
SETD5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.