Hyperphosphatasia with intellectual disability syndrome 1

Summary

Hyperphosphatasia with intellectual disability syndrome 1 (MONDO:0009398) is a disease caused by PIGV (GenCC Definitive), with 5 cohort genes. The dominant Reactome pathway is Synthesis of glycosylphosphatidylinositol (GPI) (5 cohort genes).

At a glance

• Causal gene: PIGV (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 72

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperphosphatasia with intellectual disability syndrome 1
Mondo ID	MONDO:0009398
OMIM	239300
DOID	DOID:0070433
UMLS	C4551502
MedGen	1647044
GARD	0018349
Is cancer (heuristic)	no

Also known as: HPMRS1 · hyperphosphatasia with intellectual disability syndrome 1 · hyperphosphatasia with intellectual disability syndrome type 1 · hyperphosphatasia with mental retardation syndrome 1 · hyperphosphatasia with mental retardation syndrome type 1 · hyperphosphatasia-intellectual disability syndrome caused by mutation in PIGV · PIGV hyperphosphatasia-intellectual disability syndrome

Data availability: 72 ClinVar variants · 5 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 1

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

72 retrieved; paginated sample, class counts are floors:

39 uncertain significance, 16 conflicting classifications of pathogenicity, 5 benign, 4 pathogenic, 3 pathogenic/likely pathogenic, 2 likely pathogenic, 2 benign/likely benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
694694	NM_032634.4(PIGO):c.2397A>C (p.Gln799His)	PIGO	Pathogenic	criteria provided, single submitter
1284	NM_017837.4(PIGV):c.1022C>A (p.Ala341Glu)	PIGV	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1285	NM_017837.4(PIGV):c.1154A>C (p.His385Pro)	PIGV	Pathogenic	no assertion criteria provided
1286	NM_017837.4(PIGV):c.766C>A (p.Gln256Lys)	PIGV	Pathogenic	no assertion criteria provided
1287	NM_017837.4(PIGV):c.1022C>T (p.Ala341Val)	PIGV	Pathogenic	no assertion criteria provided
30821	NM_017837.4(PIGV):c.467G>A (p.Cys156Tyr)	PIGV	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
871134	NM_017837.4(PIGV):c.607C>T (p.Arg203Cys)	PIGV	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1341513	NM_004278.4(PIGL):c.438C>A (p.Phe146Leu)	PIGL	Likely pathogenic	criteria provided, single submitter
547943	NM_017837.4(PIGV):c.55C>T (p.Arg19Cys)	PIGV	Likely pathogenic	criteria provided, single submitter
225638	NM_001127178.3(PIGG):c.2005C>T (p.Arg669Cys)	PIGG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1285152	NM_017837.4(PIGV):c.439C>T (p.Gln147Ter)	PIGV	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
135662	NM_017837.4(PIGV):c.494C>A (p.Ala165Glu)	PIGV	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1700521	NM_017837.4(PIGV):c.146C>A (p.Ser49Ter)	PIGV	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197314	NM_017837.4(PIGV):c.1277C>T (p.Pro426Leu)	PIGV	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
289202	NM_017837.4(PIGV):c.348_349delinsAG (p.Ile117Val)	PIGV	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297115	NM_017837.4(PIGV):c.348G>A (p.Leu116=)	PIGV	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
297116	NM_017837.4(PIGV):c.349A>G (p.Ile117Val)	PIGV	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
378366	NM_017837.4(PIGV):c.872A>G (p.Asn291Ser)	PIGV	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
384153	NM_017837.4(PIGV):c.879G>A (p.Pro293=)	PIGV	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
421662	NM_017837.4(PIGV):c.614A>G (p.Asn205Ser)	PIGV	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
426552	NM_017837.4(PIGV):c.1369C>T (p.Leu457Phe)	PIGV	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
449659	NM_017837.4(PIGV):c.115G>A (p.Glu39Lys)	PIGV	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
451215	NM_017837.4(PIGV):c.1147G>A (p.Val383Met)	PIGV	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
507450	NM_017837.4(PIGV):c.809G>A (p.Arg270His)	PIGV	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
874689	NM_017837.4(PIGV):c.732G>A (p.Ser244=)	PIGV	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
561082	NM_004855.5(PIGB):c.1220A>G (p.His407Arg)	PIGB	Uncertain significance	criteria provided, single submitter
1029490	NM_017837.4(PIGV):c.184G>A (p.Gly62Ser)	PIGV	Uncertain significance	criteria provided, multiple submitters, no conflicts
1164077	NM_017837.4(PIGV):c.242A>G (p.Tyr81Cys)	PIGV	Uncertain significance	criteria provided, single submitter
1319277	NM_017837.4(PIGV):c.428A>G (p.His143Arg)	PIGV	Uncertain significance	criteria provided, multiple submitters, no conflicts
1806191	NM_017837.4(PIGV):c.974del (p.Val325fs)	PIGV	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 6 · 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
PIGV	Definitive	Autosomal recessive	hyperphosphatasia with intellectual disability syndrome 1	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PIGV	Orphanet:247262	Hyperphosphatasia-intellectual disability syndrome
PIGO	Orphanet:247262	Hyperphosphatasia-intellectual disability syndrome
PIGG	Orphanet:280	Wolf-Hirschhorn syndrome
PIGG	Orphanet:488635	Early-onset epilepsy-intellectual disability-brain anomalies syndrome
PIGL	Orphanet:247262	Hyperphosphatasia-intellectual disability syndrome
PIGL	Orphanet:3474	CHIME syndrome

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PIGV	HGNC:26031	ENSG00000060642	Q9NUD9	GPI alpha-1,6-mannosyltransferase 2	gencc,clinvar
PIGO	HGNC:23215	ENSG00000165282	Q8TEQ8	GPI ethanolamine phosphate transferase 3, catalytic subunit	clinvar
PIGG	HGNC:25985	ENSG00000174227	Q5H8A4	GPI ethanolamine phosphate transferase 2, catalytic subunit	clinvar
PIGB	HGNC:8959	ENSG00000069943	Q92521	GPI alpha-1,2-mannosyltransferase 3	clinvar
PIGL	HGNC:8966	ENSG00000108474	Q9Y2B2	N-acetylglucosaminyl-phosphatidylinositol de-N-acetylase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PIGV	GPI alpha-1,6-mannosyltransferase 2	Alpha-1,6-mannosyltransferase that catalyzes the transfer of the second mannose, via an alpha-1,6 bond, from a dolichol-phosphate-mannose (Dol-P-Man) to a 2-acyl-6-(alpha-D-mannosyl-(1->4)-alpha-D-glucosaminyl)-1-(1-radyl,2-acyl-sn-glycero…
PIGO	GPI ethanolamine phosphate transferase 3, catalytic subunit	Catalytic subunit of the ethanolamine phosphate transferase 3 complex that transfers an ethanolamine phosphate (EtNP) from a phosphatidylethanolamine (PE) to the 6-OH position of the third alpha-1,2-linked mannose of the a 2-acyl-6-[alpha-…
PIGG	GPI ethanolamine phosphate transferase 2, catalytic subunit	Catalytic subunit of the ethanolamine phosphate transferase 2 complex that transfers an ethanolamine phosphate (EtNP) from a phosphatidylethanolamine (PE) to the 6-OH position of the second alpha-1,6-linked mannose of a 2-acyl-6-[6-phospho…
PIGB	GPI alpha-1,2-mannosyltransferase 3	Alpha-1,2-mannosyltransferase that catalyzes the transfer of the third mannose, via an alpha-1,2 bond, from a dolichol-phosphate-mannose (Dol-P-Man) to a 2-acyl-6-[alpha-D-mannosyl-(1->6)-2-phosphoethanolamine-alpha-D-mannosyl-(1->4)-alpha…
PIGL	N-acetylglucosaminyl-phosphatidylinositol de-N-acetylase	Catalyzes the second step of glycosylphosphatidylinositol (GPI) biosynthesis, which is the de-N-acetylation of N-acetylglucosaminyl-phosphatidylinositol.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.6

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
Phosphatase	2	33.6×	0.004
Enzyme (other)	1	2.4×	0.530
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PIGV	Other/Unknown	no		PIG-V/Gpi18
PIGO	Phosphatase	yes		Phosphodiest/P_Trfase, Alkaline_phosphatase_core_sf, PIG-O_N
PIGG	Phosphatase	yes		Phosphodiest/P_Trfase, Alkaline_phosphatase_core_sf, PIG-G_N
PIGB	Other/Unknown	no		GPI_mannosylTrfase
PIGL	Enzyme (other)	yes	3.5.1.89	GlcNAc_PI_deacetylase-related, LmbE-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right uterine tube	2
adult organism	1
male germ cell	1
sperm	1
diaphragm	1
mucosa of transverse colon	1
vena cava	1
lower esophagus	1
muscle layer of sigmoid colon	1
blood	1
calcaneal tendon	1
granulocyte	1
mucosa of stomach	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PIGV	278	ubiquitous	marker	sperm, male germ cell, adult organism
PIGO	264	ubiquitous	yes	mucosa of transverse colon, diaphragm, vena cava
PIGG	276	ubiquitous	marker	right uterine tube, muscle layer of sigmoid colon, lower esophagus
PIGB	254	ubiquitous	marker	granulocyte, blood, calcaneal tendon
PIGL	236	ubiquitous	marker	mucosa of stomach, right uterine tube, sural nerve

Protein interactions among cohort

Intra-cohort edges: 9.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PIGG	1,484
PIGO	1,302
PIGL	995
PIGV	758
PIGB	690

Intra-cohort edges

A	B	Sources
PIGB	PIGG	string_interaction
PIGB	PIGL	string_interaction
PIGB	PIGO	string_interaction
PIGB	PIGV	string_interaction
PIGG	PIGL	string_interaction
PIGG	PIGV	string_interaction
PIGL	PIGO	string_interaction
PIGL	PIGV	string_interaction
PIGO	PIGV	string_interaction

Structural data

PDB: 0 · AlphaFold-only: 5 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PIGL	Q9Y2B2	91.66
PIGV	Q9NUD9	90.22
PIGB	Q92521	88.48
PIGG	Q5H8A4	83.48
PIGO	Q8TEQ8	82.57

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 5 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of glycosylphosphatidylinositol (GPI)	5	634.4×	5e-15	PIGV, PIGO, PIGG, PIGB, PIGL

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 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	5	495.6×	2e-14	PIGV, PIGO, PIGG, PIGB, PIGL

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 1 of 5 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIGV	0	0
PIGO	0	0
PIGG	0	0
PIGB	0	0
PIGL	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PIGO	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PIGL	3.5.1.89	N-acetylglucosaminylphosphatidylinositol deacetylase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	3	PIGO, PIGG, PIGL
E	Difficult family or no structure, no drug	2	PIGV, PIGB

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PIGV	0	—
PIGO	1	—
PIGG	0	—
PIGB	0	—
PIGL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.