Hyperphosphatasia with intellectual disability syndrome 5

Summary

Hyperphosphatasia with intellectual disability syndrome 5 (MONDO:0014457) is a disease caused by PIGW (GenCC Strong), with 6 cohort genes.

At a glance

• Causal gene: PIGW (GenCC Strong)
• Cohort genes: 6
• ClinVar variants: 293

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperphosphatasia with intellectual disability syndrome 5
Mondo ID	MONDO:0014457
OMIM	616025
DOID	DOID:0070432
UMLS	C4014958
MedGen	863395
GARD	0018353
Is cancer (heuristic)	no

Also known as: GPIBD11 · HPMRS5 · hyperphosphatasia with intellectual disability syndrome 5 · hyperphosphatasia with intellectual disability syndrome type 5 · hyperphosphatasia with mental retardation syndrome 5 · hyperphosphatasia with mental retardation syndrome type 5 · hyperphosphatasia-intellectual disability syndrome caused by mutation in PIGW · PIGW hyperphosphatasia-intellectual disability syndrome

Data availability: 293 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 5

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 4, 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

293 retrieved; paginated sample, class counts are floors:

171 uncertain significance, 101 likely benign, 8 conflicting classifications of pathogenicity, 5 pathogenic, 4 benign, 2 likely pathogenic, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
156156	NM_001346754.2(PIGW):c.211A>C (p.Thr71Pro)	MYO19	Pathogenic	no assertion criteria provided
1704326	NM_001346754.2(PIGW):c.178G>A (p.Asp60Asn)	MYO19	Pathogenic	no assertion criteria provided
1704327	NM_001346754.2(PIGW):c.462A>T (p.Arg154Ser)	MYO19	Pathogenic	no assertion criteria provided
1704328	NM_001346754.2(PIGW):c.77T>C (p.Leu26Ser)	MYO19	Pathogenic	no assertion criteria provided
495299	NM_001346754.2(PIGW):c.460A>G (p.Arg154Gly)	MYO19	Pathogenic	criteria provided, single submitter
3338433	GRCh37/hg19 17q12(chr17:34842442-36065085)x3	AATF	Likely pathogenic	no assertion criteria provided
1031309	NM_001346754.2(PIGW):c.1321_1324del (p.Ile441fs)	MYO19	Likely pathogenic	criteria provided, single submitter
1498920	NM_001346754.2(PIGW):c.1282G>A (p.Val428Ile)	MYO19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1914169	NM_001346754.2(PIGW):c.413C>T (p.Ala138Val)	MYO19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2186490	NM_001346754.2(PIGW):c.309C>G (p.Cys103Trp)	MYO19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
377301	NM_001346754.2(PIGW):c.617_620del (p.Val206fs)	MYO19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
445616	NM_001346754.2(PIGW):c.646C>T (p.Arg216Ter)	MYO19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
445649	NM_001346754.2(PIGW):c.281T>A (p.Leu94Ter)	MYO19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
452328	NM_001346754.2(PIGW):c.106A>G (p.Arg36Gly)	MYO19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
715283	NM_001346754.2(PIGW):c.533C>G (p.Ser178Cys)	MYO19	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2423122	NC_000017.10:g.(?34892951)(36104875_?)dup	ACACA	Uncertain significance	criteria provided, single submitter
1412924	NC_000017.10:g.(?34892951)(36104875_?)del	DHRS11	Uncertain significance	criteria provided, single submitter
583497	NC_000017.10:g.(?34856670)(35478412_?)del	GGNBP2	Uncertain significance	criteria provided, single submitter
583936	NC_000017.10:g.(?34863642)(34916711_?)dup	GGNBP2	Uncertain significance	criteria provided, single submitter
1003144	NM_001346754.2(PIGW):c.424A>G (p.Ile142Val)	MYO19	Uncertain significance	criteria provided, single submitter
1024240	NM_001346754.2(PIGW):c.296G>C (p.Arg99Pro)	MYO19	Uncertain significance	criteria provided, single submitter
1031308	NM_001346754.2(PIGW):c.1259A>C (p.Asn420Thr)	MYO19	Uncertain significance	criteria provided, multiple submitters, no conflicts
1053872	NM_001346754.2(PIGW):c.764T>C (p.Ile255Thr)	MYO19	Uncertain significance	criteria provided, single submitter
1056682	NM_001346754.2(PIGW):c.937G>C (p.Val313Leu)	MYO19	Uncertain significance	criteria provided, single submitter
1303678	NM_001346754.2(PIGW):c.647G>A (p.Arg216Gln)	MYO19	Uncertain significance	criteria provided, multiple submitters, no conflicts
1303679	NM_001346754.2(PIGW):c.659T>G (p.Ile220Arg)	MYO19	Uncertain significance	criteria provided, multiple submitters, no conflicts
1346140	NM_001346754.2(PIGW):c.460AGA[1] (p.Arg155del)	MYO19	Uncertain significance	criteria provided, single submitter
1346677	NM_001346754.2(PIGW):c.677A>G (p.Gln226Arg)	MYO19	Uncertain significance	criteria provided, single submitter
1347431	NM_001346754.2(PIGW):c.910G>A (p.Glu304Lys)	MYO19	Uncertain significance	criteria provided, multiple submitters, no conflicts
1347503	NM_001346754.2(PIGW):c.1450_1451del (p.Met484fs)	MYO19	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
PIGW	Strong	Autosomal recessive	hyperphosphatasia with intellectual disability syndrome 5	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PIGW	Orphanet:247262	Hyperphosphatasia-intellectual disability syndrome
PIGW	Orphanet:83639	Hypercoagulability syndrome due to glycosylphosphatidylinositol deficiency

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PIGW	HGNC:23213	ENSG00000277161	Q7Z7B1	Glucosaminyl-phosphatidylinositol-acyltransferase PIGW	gencc,clinvar
AATF	HGNC:19235	ENSG00000275700	Q9NY61	Protein AATF	clinvar
GGNBP2	HGNC:19357	ENSG00000278311	Q9H3C7	Gametogenetin-binding protein 2	clinvar
MYO19	HGNC:26234	ENSG00000278259	Q96H55	Unconventional myosin-XIX	clinvar
DHRS11	HGNC:28639	ENSG00000278535	Q6UWP2	Dehydrogenase/reductase SDR family member 11	clinvar
ACACA	HGNC:84	ENSG00000278540	Q13085	Acetyl-CoA carboxylase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PIGW	Glucosaminyl-phosphatidylinositol-acyltransferase PIGW	Acyltransferase that catalyzes the acyl transfer from an acyl-CoA at the 2-OH position of the inositol ring of a 6-(alpha-D-glucosaminyl)-1-(1,2-diacyl-sn-glycero-3-phospho)-1D-myo-inositol (glucosaminyl phosphatidylinositol, GlcN-PI) to g…
AATF	Protein AATF	Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit.
GGNBP2	Gametogenetin-binding protein 2	May be involved in spermatogenesis.
MYO19	Unconventional myosin-XIX	Actin-based motor molecule with ATPase activity that localizes to the mitochondrion outer membrane.
DHRS11	Dehydrogenase/reductase SDR family member 11	Catalyzes the conversion of the 17-keto group of estrone, 4- and 5-androstenes and 5-alpha-androstanes into their 17-beta-hydroxyl metabolites and the conversion of the 3-keto group of 3-, 3,17- and 3,20- diketosteroids into their 3beta-hy…
ACACA	Acetyl-CoA carboxylase 1	Cytosolic enzyme that catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the first and rate-limiting step of de novo fatty acid biosynthesis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 5 · Druggable fraction: 0.17

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	5	1.5×	0.348
Enzyme (other)	1	2.0×	0.407

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PIGW	Other/Unknown	no		PIGW/GWT1
AATF	Other/Unknown	no		AATF_C, AATF, AATF/Bfr2
GGNBP2	Other/Unknown	no		GGNBP2
MYO19	Other/Unknown	no		Myosin_head_motor_dom-like, P-loop_NTPase, MYSc_Myo19
DHRS11	Other/Unknown	no		SDR_fam, Sc_DH/Rdtase_CS, NAD(P)-bd_dom_sf
ACACA	Enzyme (other)	yes	6.4.1.2	Biotin_lipoyl, Biotin_BS, CPAse_ATP-bd

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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endometrium	1
gastrocnemius	1
islet of Langerhans	1
granulocyte	1
leukocyte	1
monocyte	1
left testis	1
right testis	1
testis	1
metanephros cortex	1
skin of abdomen	1
skin of leg	1
duodenum	1
mucosa of transverse colon	1
rectum	1
adrenal tissue	1
cortical plate	1
ganglionic eminence	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PIGW	134	ubiquitous	yes	islet of Langerhans, endometrium, gastrocnemius
AATF	134	ubiquitous	marker	monocyte, leukocyte, granulocyte
GGNBP2	134	ubiquitous	marker	left testis, right testis, testis
MYO19	244	ubiquitous	yes	skin of leg, skin of abdomen, metanephros cortex
DHRS11	134	ubiquitous	marker	duodenum, mucosa of transverse colon, rectum
ACACA	134	ubiquitous	marker	cortical plate, adrenal tissue, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACACA	4,113
DHRS11	3,492
AATF	3,194
MYO19	3,000
GGNBP2	2,235
PIGW	1,715

Intra-cohort edges

A	B	Sources
AATF	GGNBP2	string_interaction
DHRS11	GGNBP2	string_interaction
DHRS11	MYO19	string_interaction
GGNBP2	MYO19	string_interaction
GGNBP2	PIGW	string_interaction
MYO19	PIGW	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACACA	Q13085	10
AATF	Q9NY61	3
GGNBP2	Q9H3C7	1
DHRS11	Q6UWP2	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PIGW	Q7Z7B1	87.17
MYO19	Q96H55	76.93

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 28. Enrichment computed across 6 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defects in biotin (Btn) metabolism	1	571.0×	0.014	ACACA
RHOT1 GTPase cycle	1	571.0×	0.014	MYO19
Miro GTPase Cycle	1	571.0×	0.014	MYO19
Defective HLCS causes multiple carboxylase deficiency	1	407.9×	0.014	ACACA
RHOT2 GTPase cycle	1	407.9×	0.014	MYO19
ChREBP activates metabolic gene expression	1	317.2×	0.015	ACACA
Biotin transport and metabolism	1	259.6×	0.015	ACACA
Carnitine shuttle	1	190.3×	0.018	ACACA
Synthesis of glycosylphosphatidylinositol (GPI)	1	158.6×	0.019	PIGW
Defects in vitamin and cofactor metabolism	1	150.3×	0.019	ACACA
Fatty acyl-CoA biosynthesis	1	109.8×	0.023	ACACA
Regulation of cholesterol biosynthesis by SREBP (SREBF)	1	79.3×	0.029	ACACA
Activation of gene expression by SREBF (SREBP)	1	64.9×	0.033	ACACA
Cell death signalling via NRAGE, NRIF and NADE	1	54.9×	0.035	AATF
p75 NTR receptor-mediated signalling	1	46.8×	0.035	AATF
NRAGE signals death through JNK	1	46.0×	0.035	AATF
Metabolism of water-soluble vitamins and cofactors	1	45.3×	0.035	ACACA
Integration of energy metabolism	1	43.9×	0.035	ACACA
Death Receptor Signaling	1	34.8×	0.040	AATF
Metabolism of steroids	1	34.4×	0.040	ACACA
Fatty acid metabolism	1	32.8×	0.040	ACACA
Metabolism of vitamins and cofactors	1	29.1×	0.043	ACACA
Diseases of metabolism	1	20.1×	0.059	ACACA
Signal Transduction	2	5.1×	0.059	AATF, MYO19
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	8.4×	0.128	MYO19
Metabolism of lipids	1	7.9×	0.130	ACACA
Disease	1	3.3×	0.283	ACACA
Metabolism	1	2.9×	0.302	ACACA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrion migration along actin filament	1	2808.7×	0.011	MYO19
malonyl-CoA biosynthetic process	1	1404.3×	0.011	ACACA
GPI anchor metabolic process	1	936.2×	0.011	PIGW
negative regulation of receptor signaling pathway via STAT	1	561.7×	0.011	GGNBP2
mitocytosis	1	468.1×	0.011	MYO19
acetyl-CoA metabolic process	1	401.2×	0.011	ACACA
negative regulation of amyloid precursor protein biosynthetic process	1	351.1×	0.011	AATF
regulation of mitochondrial fission	1	351.1×	0.011	MYO19
fatty-acyl-CoA biosynthetic process	1	312.1×	0.011	ACACA
embryonic cleavage	1	280.9×	0.011	AATF
estrogen biosynthetic process	1	255.3×	0.011	DHRS11
cellular response to prostaglandin E stimulus	1	140.4×	0.018	ACACA
labyrinthine layer blood vessel development	1	133.8×	0.018	GGNBP2
steroid biosynthetic process	1	100.3×	0.021	DHRS11
tissue homeostasis	1	93.6×	0.021	ACACA
negative regulation of apoptotic signaling pathway	1	93.6×	0.021	AATF
GPI anchor biosynthetic process	1	82.6×	0.022	PIGW
regulation of cytokinesis	1	70.2×	0.024	MYO19
fatty acid biosynthetic process	1	58.5×	0.027	ACACA
lipid homeostasis	1	56.2×	0.027	ACACA
regulation of mitotic cell cycle	1	40.1×	0.035	AATF
protein homotetramerization	1	39.6×	0.035	ACACA
ribosomal small subunit biogenesis	1	38.0×	0.035	AATF
actin filament organization	1	19.8×	0.064	MYO19
protein localization to plasma membrane	1	18.1×	0.067	PIGW
endocytosis	1	15.9×	0.073	MYO19
negative regulation of gene expression	1	11.5×	0.096	GGNBP2
negative regulation of cell population proliferation	1	7.0×	0.149	GGNBP2
cell adhesion	1	6.2×	0.160	AATF
spermatogenesis	1	5.9×	0.164	GGNBP2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 6 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ACACA	BEMPEDOIC ACID

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACACA	4	4
PIGW	0	0
AATF	0	0
GGNBP2	0	0
MYO19	0	0
DHRS11	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEMPEDOIC ACID	4	ACACA
PF-05175157	2	ACACA
FIRSOCOSTAT	2	ACACA
CLESACOSTAT	2	ACACA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ACACA	71	Binding:71
PIGW	1	ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ACACA	6.4.1.2	acetyl-CoA carboxylase

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

4 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.

Compound	Max phase	Cohort target (bioactivity)
BEMPEDOIC ACID	4	ACACA
PF-05175157	2	ACACA
FIRSOCOSTAT	2	ACACA
CLESACOSTAT	2	ACACA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ACACA
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	5	PIGW, AATF, GGNBP2, MYO19, DHRS11

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)
PIGW	1	—
AATF	0	—
GGNBP2	0	—
MYO19	0	—
DHRS11	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.