Acromesomelic dysplasia 4

Summary

Acromesomelic dysplasia 4 (MONDO:0030553) is a disease caused by PRKG2 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: PRKG2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	acromesomelic dysplasia 4
Mondo ID	MONDO:0030553
OMIM	619636
DOID	DOID:0081238
UMLS	C5562028
MedGen	1794238
GARD	0025602
Is cancer (heuristic)	no

Also known as: AMD4

Data availability: 9 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › acromesomelic dysplasia › acromesomelic dysplasia 4

Related subtypes (7): Osebold-Remondini syndrome, acromesomelic dysplasia 2A, acromesomelic dysplasia 2C, Hunter-Thompson type, acromesomelic dysplasia 2B, acromesomelic dysplasia 1, Maroteaux type, acromesomelic dysplasia 3, acromesomelic dysplasia, Campailla Martinelli type

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

9 retrieved; paginated sample, class counts are floors:

3 pathogenic, 3 likely pathogenic, 3 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1326257	NM_006259.3(PRKG2):c.1705C>T (p.Arg569Ter)	PRKG2	Pathogenic	no assertion criteria provided
1326258	NM_006259.3(PRKG2):c.491dup (p.Asn164fs)	PRKG2	Pathogenic	no assertion criteria provided
2502276	NM_006259.3(PRKG2):c.1154+1G>A	PRKG2	Pathogenic	criteria provided, single submitter
2501812	NM_006259.3(PRKG2):c.1409T>G (p.Val470Gly)	PRKG2	Likely pathogenic	criteria provided, single submitter
4082151	NM_006259.3(PRKG2):c.1630G>T (p.Asp544Tyr)	PRKG2	Likely pathogenic	criteria provided, single submitter
4537385	NM_006259.3(PRKG2):c.1074del (p.Ala359fs)	PRKG2	Likely pathogenic	criteria provided, single submitter
4278306	NM_016310.5(POLR3K):c.322G>C (p.Asp108His)	POLR3K	Uncertain significance	criteria provided, single submitter
3393264	NM_006259.3(PRKG2):c.848G>A (p.Ser283Asn)	PRKG2	Uncertain significance	criteria provided, single submitter
3892186	NM_145168.3(SDR42E1):c.*1075_*1076insCAAAAATAACCTAACTAGTGATAAAGTGTATATACTTTAAGAGC	SDR42E1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 0 · 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
PRKG2	Strong	Autosomal recessive	acromesomelic dysplasia 4	4

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
PRKG2	HGNC:9416	ENSG00000138669	Q13237	cGMP-dependent protein kinase 2	gencc,clinvar
POLR3K	HGNC:14121	ENSG00000161980	Q9Y2Y1	DNA-directed RNA polymerase III subunit RPC10	clinvar
SDR42E1	HGNC:29834	ENSG00000184860	Q8WUS8	Short-chain dehydrogenase/reductase family 42E member 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PRKG2	cGMP-dependent protein kinase 2	Crucial regulator of intestinal secretion and bone growth.
POLR3K	DNA-directed RNA polymerase III subunit RPC10	Core component of RNA polymerase III (Pol III) which synthesizes small non-coding RNAs using the four ribonucleoside triphosphates as substrates.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Kinase	1	9.2×	0.313
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRKG2	Kinase	yes	2.7.11.12	cNMP-bd_dom, Prot_kinase_dom, AGC-kinase_C
POLR3K	Transcription factor	no		Znf_TFIIS, Zn_ribbon_RPB9, Rpa12/Rpb9/Rpc10/TFS
SDR42E1	Other/Unknown	no		3Beta_OHSteriod_DH/Estase, NAD(P)-bd_dom_sf, Lipid_A_modif_metabolic_enz

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
jejunal mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1
tibia	1
mucosa of transverse colon	1
prefrontal cortex	1
primordial germ cell in gonad	1
epithelial cell of pancreas	1
islet of Langerhans	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRKG2	167	broad	marker	jejunal mucosa, male germ line stem cell (sensu Vertebrata) in testis, tibia
POLR3K	277	ubiquitous	marker	mucosa of transverse colon, prefrontal cortex, primordial germ cell in gonad
SDR42E1	152	broad	marker	upper leg skin, epithelial cell of pancreas, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SDR42E1	2,602
POLR3K	2,332
PRKG2	1,678

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLR3K	Q9Y2Y1	29
PRKG2	Q13237	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SDR42E1	Q8WUS8	89.38

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. Enrichment computed across 3 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
Metabolism of cofactors	1	951.7×	0.013	PRKG2
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation	1	571.0×	0.013	PRKG2
Nitric oxide stimulates guanylate cyclase	1	407.9×	0.013	PRKG2
cGMP effects	1	356.9×	0.013	PRKG2
RNA Polymerase III Chain Elongation	1	317.2×	0.013	POLR3K
RNA Polymerase III Transcription Termination	1	248.3×	0.013	POLR3K
RAS processing	1	237.9×	0.013	PRKG2
RNA Polymerase III Transcription Initiation From Type 2 Promoter	1	211.5×	0.013	POLR3K
RNA Polymerase III Transcription Initiation From Type 1 Promoter	1	203.9×	0.013	POLR3K
RNA Polymerase III Transcription Initiation From Type 3 Promoter	1	203.9×	0.013	POLR3K
RNA Polymerase III Transcription Initiation	1	167.9×	0.013	POLR3K
RNA Polymerase III Transcription	1	163.1×	0.013	POLR3K
Beta-catenin independent WNT signaling	1	146.4×	0.013	PRKG2
Cytosolic sensors of pathogen-associated DNA	1	142.8×	0.013	POLR3K
Platelet homeostasis	1	139.3×	0.013	PRKG2
RNA Polymerase III Abortive And Retractive Initiation	1	139.3×	0.013	POLR3K
Maturation of DENV proteins	1	105.7×	0.016	PRKG2
Ca2+ pathway	1	89.2×	0.018	PRKG2
MAPK1/MAPK3 signaling	1	65.6×	0.023	PRKG2
Metabolism of vitamins and cofactors	1	58.3×	0.025	PRKG2
Signaling by WNT	1	56.0×	0.025	PRKG2
MAPK family signaling cascades	1	51.4×	0.026	PRKG2
RAF/MAP kinase cascade	1	30.5×	0.041	PRKG2
Hemostasis	1	18.0×	0.066	PRKG2
Innate Immune System	1	12.8×	0.089	POLR3K
Gene expression (Transcription)	1	8.9×	0.122	POLR3K
Immune System	1	6.5×	0.159	POLR3K
Metabolism	1	5.8×	0.171	PRKG2
Signal Transduction	1	5.1×	0.187	PRKG2

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
tetrahydrobiopterin metabolic process	1	2808.7×	0.002	PRKG2
negative regulation of chloride transport	1	2808.7×	0.002	PRKG2
positive regulation of protein localization	1	468.1×	0.008	PRKG2
positive regulation of chondrocyte differentiation	1	267.5×	0.009	PRKG2
transcription by RNA polymerase III	1	255.3×	0.009	POLR3K
steroid biosynthetic process	1	200.6×	0.009	SDR42E1
protein localization to plasma membrane	1	36.2×	0.043	PRKG2
defense response to virus	1	23.1×	0.059	POLR3K
intracellular signal transduction	1	12.7×	0.094	PRKG2
innate immune response	1	11.2×	0.095	POLR3K
signal transduction	1	5.3×	0.176	PRKG2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 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
PRKG2	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRKG2	10	4
POLR3K	0	0
SDR42E1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	PRKG2
RUXOLITINIB	4	PRKG2
MIDOSTAURIN	4	PRKG2
ENZASTAURIN	3	PRKG2
LESTAURTINIB	3	PRKG2
RUBOXISTAURIN	3	PRKG2
R-406	2	PRKG2
KW-2449	1	PRKG2
GSK-690693	1	PRKG2
5-(6-BENZOTHIAZOLYLMETHYLENE)-3,5-DIHYDRO-2-(((1S)-1-(METHOXYMETHYL)-3-METHYLBUTYL)AMINO)-4H-IMIDAZOL-4-ONE, (5Z)-	1	PRKG2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PRKG2	171	Binding:170, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PRKG2	2.7.11.12	cGMP-dependent protein kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PRKG2	171

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

10 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)
FEDRATINIB	4	PRKG2
RUXOLITINIB	4	PRKG2
MIDOSTAURIN	4	PRKG2
ENZASTAURIN	3	PRKG2
LESTAURTINIB	3	PRKG2
RUBOXISTAURIN	3	PRKG2
R-406	2	PRKG2
KW-2449	1	PRKG2
GSK-690693	1	PRKG2
5-(6-BENZOTHIAZOLYLMETHYLENE)-3,5-DIHYDRO-2-(((1S)-1-(METHOXYMETHYL)-3-METHYLBUTYL)AMINO)-4H-IMIDAZOL-4-ONE, (5Z)-	1	PRKG2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PRKG2
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	2	POLR3K, SDR42E1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
POLR3K	0	—
SDR42E1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.