Hyperphosphatasia with intellectual disability syndrome 2

Summary

Hyperphosphatasia with intellectual disability syndrome 2 (MONDO:0013882) is a disease caused by PIGO (GenCC Definitive), with 5 cohort genes.

At a glance

• Causal gene: PIGO (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 928

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperphosphatasia with intellectual disability syndrome 2
Mondo ID	MONDO:0013882
OMIM	614749
DOID	DOID:0070434
UMLS	C3553637
MedGen	766551
GARD	0018351
Is cancer (heuristic)	no

Also known as: HPMRS2 · hyperphosphatasia with intellectual disability syndrome 2 · hyperphosphatasia with intellectual disability syndrome type 2 · hyperphosphatasia with mental retardation syndrome 2 · hyperphosphatasia with mental retardation syndrome type 2 · hyperphosphatasia-intellectual disability syndrome caused by mutation in PIGO · PIGO hyperphosphatasia-intellectual disability syndrome

Data availability: 928 ClinVar variants · 4 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 2

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

600 retrieved; paginated sample, class counts are floors:

271 likely benign, 249 uncertain significance, 36 pathogenic, 16 conflicting classifications of pathogenicity, 11 benign, 8 benign/likely benign, 5 pathogenic/likely pathogenic, 4 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068540	NM_032634.4(PIGO):c.2257del (p.Ser753fs)	PIGO	Pathogenic	criteria provided, single submitter
1070437	NM_032634.4(PIGO):c.1445_1449del (p.Leu482fs)	PIGO	Pathogenic	criteria provided, single submitter
1070693	NM_032634.4(PIGO):c.773del (p.Val258fs)	PIGO	Pathogenic	criteria provided, single submitter
1072029	NM_032634.4(PIGO):c.2602_2605del (p.Leu868fs)	PIGO	Pathogenic	criteria provided, single submitter
1076728	NM_032634.4(PIGO):c.2360_2363del (p.Pro787fs)	PIGO	Pathogenic	criteria provided, single submitter
1392155	NM_032634.4(PIGO):c.1329G>A (p.Trp443Ter)	PIGO	Pathogenic	criteria provided, single submitter
1451783	NM_032634.4(PIGO):c.1942del (p.Cys648fs)	PIGO	Pathogenic	criteria provided, single submitter
1454378	NM_032634.4(PIGO):c.1222C>T (p.Gln408Ter)	PIGO	Pathogenic	criteria provided, single submitter
1457267	NM_032634.4(PIGO):c.1087C>T (p.Gln363Ter)	PIGO	Pathogenic	criteria provided, single submitter
1903867	NM_032634.4(PIGO):c.894_895del (p.Phe299fs)	PIGO	Pathogenic	criteria provided, single submitter
1909826	NM_032634.4(PIGO):c.36G>A (p.Trp12Ter)	PIGO	Pathogenic	criteria provided, single submitter
1945917	NM_032634.4(PIGO):c.1126C>T (p.Arg376Ter)	PIGO	Pathogenic	criteria provided, single submitter
1956756	NM_032634.4(PIGO):c.1361dup (p.Thr455fs)	PIGO	Pathogenic	criteria provided, single submitter
2017642	NM_032634.4(PIGO):c.309del (p.Lys103fs)	PIGO	Pathogenic	criteria provided, single submitter
2034143	NM_032634.4(PIGO):c.2413C>T (p.Gln805Ter)	PIGO	Pathogenic	criteria provided, single submitter
2106509	NM_032634.4(PIGO):c.1923C>A (p.Cys641Ter)	PIGO	Pathogenic	criteria provided, single submitter
2120565	NM_032634.4(PIGO):c.2953A>T (p.Arg985Ter)	PIGO	Pathogenic	criteria provided, single submitter
2146203	NM_032634.4(PIGO):c.1114C>T (p.Gln372Ter)	PIGO	Pathogenic	criteria provided, single submitter
2415324	NM_032634.4(PIGO):c.28del (p.Leu10fs)	PIGO	Pathogenic	criteria provided, single submitter
2710215	NM_032634.4(PIGO):c.2217del (p.Ser740fs)	PIGO	Pathogenic	criteria provided, single submitter
2717350	NM_032634.4(PIGO):c.2442_2457del (p.Arg814fs)	PIGO	Pathogenic	criteria provided, single submitter
2732848	NM_032634.4(PIGO):c.3067C>T (p.Gln1023Ter)	PIGO	Pathogenic	criteria provided, single submitter
2734011	NM_032634.4(PIGO):c.2368C>T (p.Gln790Ter)	PIGO	Pathogenic	criteria provided, single submitter
2754191	NM_032634.4(PIGO):c.2117G>A (p.Trp706Ter)	PIGO	Pathogenic	criteria provided, single submitter
2763210	NM_032634.4(PIGO):c.1184del (p.Gln395fs)	PIGO	Pathogenic	criteria provided, single submitter
2786782	NM_032634.4(PIGO):c.1189C>T (p.Gln397Ter)	PIGO	Pathogenic	criteria provided, single submitter
2815586	NM_032634.4(PIGO):c.985del (p.Leu329fs)	PIGO	Pathogenic	criteria provided, single submitter
2839158	NM_032634.4(PIGO):c.1361del (p.Gly454fs)	PIGO	Pathogenic	criteria provided, single submitter
2839262	NM_032634.4(PIGO):c.327_336del (p.Ile110fs)	PIGO	Pathogenic	criteria provided, single submitter
286126	NM_032634.4(PIGO):c.1810dup (p.Arg604fs)	PIGO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · 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
PIGO	Definitive	Autosomal recessive	hyperphosphatasia with intellectual disability syndrome 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PIGO	Orphanet:247262	Hyperphosphatasia-intellectual disability syndrome
DDRGK1	Orphanet:93352	Spondyloepimetaphyseal dysplasia, Shohat type

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
PIGO	HGNC:23215	ENSG00000165282	Q8TEQ8	GPI ethanolamine phosphate transferase 3, catalytic subunit	gencc,clinvar
DDRGK1	HGNC:16110	ENSG00000198171	Q96HY6	DDRGK domain-containing protein 1	clinvar
RUSC2	HGNC:23625	ENSG00000198853	Q8N2Y8	AP-4 complex accessory subunit RUSC2	clinvar
CIMIP2B	HGNC:34242	ENSG00000215187	A8MTA8	Ciliary microtubule inner protein 2B	clinvar
SPATA31F1	HGNC:41911	ENSG00000205108	Q6ZU69	Protein SPATA31F1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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-…
DDRGK1	DDRGK domain-containing protein 1	Component of the UFM1 ribosome E3 ligase (UREL) complex, a multiprotein complex that catalyzes ufmylation of endoplasmic reticulum-docked proteins.
RUSC2	AP-4 complex accessory subunit RUSC2	Associates with the adapter-like complex 4 (AP-4) and may therefore play a role in vesicular trafficking of proteins at the trans-Golgi network.
CIMIP2B	Ciliary microtubule inner protein 2B	Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.2

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	1	16.8×	0.175
Scaffold/PPI	1	3.5×	0.386
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PIGO	Phosphatase	yes		Phosphodiest/P_Trfase, Alkaline_phosphatase_core_sf, PIG-O_N
DDRGK1	Other/Unknown	no		DDRGK_dom-contain, WH-like_DNA-bd_sf, WH_DNA-bd_sf
RUSC2	Scaffold/PPI	no		SH3_domain, Run_dom, SH3-like_dom_sf
CIMIP2B	Other/Unknown	no		CMI2A-C-like_dom
SPATA31F1	Other/Unknown	no		SPATA31-like, SPATA31

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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right adrenal gland	2
right adrenal gland cortex	2
diaphragm	1
mucosa of transverse colon	1
vena cava	1
tendon of biceps brachii	1
cortical plate	1
popliteal artery	1
right frontal lobe	1
adrenal tissue	1
left testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PIGO	264	ubiquitous	yes	mucosa of transverse colon, diaphragm, vena cava
DDRGK1	271	ubiquitous	marker	tendon of biceps brachii, right adrenal gland, right adrenal gland cortex
RUSC2	237	ubiquitous	marker	cortical plate, right frontal lobe, popliteal artery
CIMIP2B	167	tissue_specific	marker	adrenal tissue, right adrenal gland cortex, right adrenal gland
SPATA31F1	25	tissue_specific	yes	left testis, right testis, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DDRGK1	4,153
RUSC2	1,916
PIGO	1,302
CIMIP2B	342
SPATA31F1	222

Structural data

PDB: 3 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DDRGK1	Q96HY6	8
CIMIP2B	A8MTA8	2
RUSC2	Q8N2Y8	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PIGO	Q8TEQ8	82.57
SPATA31F1	Q6ZU69	42.69

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 5 evidence-associated genes (2 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 2 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)	1	317.2×	0.006	PIGO
RHOA GTPase cycle	1	37.3×	0.027	DDRGK1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of I-kappaB phosphorylation	1	8426.0×	0.003	DDRGK1
positive regulation of reticulophagy	1	2808.7×	0.003	DDRGK1
positive regulation of protein localization to endoplasmic reticulum	1	2808.7×	0.003	DDRGK1
positive regulation of plasma cell differentiation	1	2106.5×	0.003	DDRGK1
obsolete positive regulation of proteolysis involved in protein catabolic process	1	2106.5×	0.003	DDRGK1
protein K69-linked ufmylation	1	1685.2×	0.003	DDRGK1
negative regulation of IRE1-mediated unfolded protein response	1	1404.3×	0.003	DDRGK1
protein ufmylation	1	1203.7×	0.003	DDRGK1
protein localization to endoplasmic reticulum	1	1053.2×	0.003	DDRGK1
regulation of intracellular estrogen receptor signaling pathway	1	936.2×	0.003	DDRGK1
negative regulation of PERK-mediated unfolded protein response	1	702.2×	0.004	DDRGK1
positive regulation of cell cycle G1/S phase transition	1	561.7×	0.004	DDRGK1
ribosome disassembly	1	495.6×	0.004	DDRGK1
positive regulation of proteasomal protein catabolic process	1	495.6×	0.004	DDRGK1
reticulophagy	1	351.1×	0.006	DDRGK1
GPI anchor biosynthetic process	1	247.8×	0.007	PIGO
rescue of stalled cytosolic ribosome	1	240.7×	0.007	DDRGK1
negative regulation of proteasomal ubiquitin-dependent protein catabolic process	1	200.6×	0.008	DDRGK1
cartilage development	1	125.8×	0.013	DDRGK1
positive regulation of proteasomal ubiquitin-dependent protein catabolic process	1	105.3×	0.014	DDRGK1
obsolete positive regulation of NF-kappaB transcription factor activity	1	102.8×	0.014	DDRGK1
response to endoplasmic reticulum stress	1	83.4×	0.016	DDRGK1
regulation of protein stability	1	62.9×	0.021	DDRGK1
positive regulation of canonical NF-kappaB signal transduction	1	36.3×	0.034	DDRGK1
negative regulation of gene expression	1	34.5×	0.034	DDRGK1
positive regulation of cell migration	1	30.9×	0.037	DDRGK1
positive regulation of gene expression	1	19.4×	0.057	DDRGK1
negative regulation of apoptotic process	1	17.4×	0.061	DDRGK1
positive regulation of cell population proliferation	1	16.8×	0.061	DDRGK1
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	DDRGK1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 5 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIGO	0	0
DDRGK1	0	0
RUSC2	0	0
CIMIP2B	0	0
SPATA31F1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PIGO	1	Binding:1
DDRGK1	1	Binding:1

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	1	PIGO
E	Difficult family or no structure, no drug	4	DDRGK1, RUSC2, CIMIP2B, SPATA31F1

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)
PIGO	1	—
DDRGK1	1	—
RUSC2	0	—
CIMIP2B	0	—
SPATA31F1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.