Short stature with nonspecific skeletal abnormalities 1

Summary

Short stature with nonspecific skeletal abnormalities 1 (MONDO:0014551) is a disease caused by NPR2 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: NPR2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 10

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	short stature with nonspecific skeletal abnormalities 1
Mondo ID	MONDO:0014551
OMIM	616255
Is cancer (heuristic)	no

Also known as: short stature with nonspecific skeletal abnormalities 1 · SNSK

Data availability: 10 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › short stature with nonspecific skeletal abnormalities › short stature with nonspecific skeletal abnormalities 1

Related subtypes (1): brachydactyly type A1

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

10 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 2 pathogenic, 1 conflicting classifications of pathogenicity, 1 likely pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3778822	NM_201566.3(SLC16A13):c.24del (p.Asp9fs)	LOC130060100	Pathogenic	criteria provided, single submitter
4755517	NM_003995.4(NPR2):c.2005C>T (p.Arg669Ter)	NPR2	Pathogenic	criteria provided, single submitter
873132	NM_003995.4(NPR2):c.1887+2T>A	NPR2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4819364	NM_003995.4(NPR2):c.2945A>T (p.Asp982Val)	NPR2	Likely pathogenic	criteria provided, single submitter
193262	NM_003995.4(NPR2):c.64G>T (p.Ala22Ser)	NPR2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1000706	NM_003995.4(NPR2):c.953G>A (p.Arg318Gln)	NPR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1064023	NM_003995.4(NPR2):c.2363G>A (p.Arg788His)	NPR2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3891854	NM_003995.4(NPR2):c.2436G>C (p.Leu812Phe)	NPR2	Uncertain significance	criteria provided, single submitter
4532126	NM_003995.4(NPR2):c.1859G>A (p.Arg620His)	NPR2	Uncertain significance	criteria provided, single submitter
951022	NM_003995.4(NPR2):c.1636A>T (p.Asn546Tyr)	NPR2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 31 · Orphanet: 3 · 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
NPR2	Strong	Autosomal dominant	tall stature-scoliosis-macrodactyly of the great toes syndrome	12
NPRL2	Strong	Autosomal dominant	tall stature-scoliosis-macrodactyly of the great toes syndrome	17
NPPC	Limited	Autosomal dominant	short stature with nonspecific skeletal abnormalities 1	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NPRL2	Orphanet:98820	Familial focal epilepsy with variable foci
NPR2	Orphanet:329191	Tall stature-long halluces-multiple extra-epiphyses syndrome
NPR2	Orphanet:40	Acromesomelic dysplasia, Maroteaux type

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
NPRL2	HGNC:24969	ENSG00000114388	Q8WTW4	GATOR1 complex protein NPRL2	gencc,clinvar
NPR2	HGNC:7944	ENSG00000159899	P20594	Atrial natriuretic peptide receptor 2	gencc,clinvar
NPPC	HGNC:7941	ENSG00000163273	P23582	C-type natriuretic peptide	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NPRL2	GATOR1 complex protein NPRL2	Catalytic component of the GATOR1 complex, a multiprotein complex that functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway.
NPR2	Atrial natriuretic peptide receptor 2	Receptor for the C-type natriuretic peptide NPPC/CNP hormone.
NPPC	C-type natriuretic peptide	Hormone which plays a role in endochondral ossification through regulation of cartilaginous growth plate chondrocytes proliferation and differentiation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · 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×	0.209
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NPRL2	Other/Unknown	no		NPR2-like
NPR2	Kinase	yes	4.6.1.2	Prot_kinase_dom, A/G_cyclase, ANPR/GUC
NPPC	Other/Unknown	no		Natr_peptide, C_natriurtcpep, Natr_peptide_CS

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
cerebellar hemisphere	2
right hemisphere of cerebellum	2
granulocyte	1
right uterine tube	1
C1 segment of cervical spinal cord	1
male germ line stem cell (sensu Vertebrata) in testis	1
prefrontal cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NPRL2	285	ubiquitous	marker	granulocyte, right hemisphere of cerebellum, cerebellar hemisphere
NPR2	267	ubiquitous	marker	right uterine tube, right hemisphere of cerebellum, cerebellar hemisphere
NPPC	131	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, C1 segment of cervical spinal cord, prefrontal cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NPRL2	1,222
NPR2	885
NPPC	750

Intra-cohort edges

A	B	Sources
NPPC	NPR2	biogrid_interaction, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NPRL2	Q8WTW4	10
NPPC	P23582	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NPR2	P20594	84.00

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Physiological factors	2	447.8×	3e-05	NPR2, NPPC
Cardiac conduction	2	72.5×	5e-04	NPR2, NPPC
Muscle contraction	2	51.4×	7e-04	NPR2, NPPC
Amino acids regulate mTORC1	1	66.8×	0.015	NPRL2

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
cumulus cell differentiation	2	3744.9×	2e-06	NPR2, NPPC
gastric emptying	2	3744.9×	2e-06	NPR2, NPPC
c-di-GMP signaling	2	3744.9×	2e-06	NPR2, NPPC
negative regulation of meiotic cell cycle	2	2808.7×	2e-06	NPR2, NPPC
negative regulation of oocyte maturation	2	2246.9×	3e-06	NPR2, NPPC
meiotic cell cycle process involved in oocyte maturation	2	1872.4×	4e-06	NPR2, NPPC
cGMP biosynthetic process	2	936.2×	2e-05	NPR2, NPPC
receptor guanylyl cyclase signaling pathway	2	864.2×	2e-05	NPR2, NPPC
chromosome organization	2	387.4×	7e-05	NPR2, NPPC
blood vessel remodeling	2	255.3×	2e-04	NPR2, NPPC
vestibulocochlear nerve maturation	1	5617.3×	0.001	NPR2
response to luteinizing hormone	1	2808.7×	0.002	NPR2
activation of meiosis involved in egg activation	1	2808.7×	0.002	NPR2
multicellular organismal locomotion	1	1872.4×	0.003	NPPC
cellular response to glycoprotein	1	1872.4×	0.003	NPPC
growth plate cartilage chondrocyte differentiation	1	1404.3×	0.003	NPPC
growth plate cartilage chondrocyte proliferation	1	1404.3×	0.003	NPPC
negative regulation of kinase activity	1	1404.3×	0.003	NPRL2
genitalia morphogenesis	1	1123.5×	0.004	NPR2
obsolete positive regulation of cGMP-mediated signaling	1	802.5×	0.004	NPPC
female genitalia development	1	802.5×	0.004	NPR2
bone growth	1	802.5×	0.004	NPR2
growth plate cartilage development	1	702.2×	0.004	NPR2
cellular response to cGMP	1	702.2×	0.004	NPR2
response to fibroblast growth factor	1	702.2×	0.004	NPR2
response to oxygen-glucose deprivation	1	702.2×	0.004	NPPC
response to salt	1	702.2×	0.004	NPR2
lymph vessel development	1	624.1×	0.004	NPR2
vascular wound healing	1	624.1×	0.004	NPR2
negative regulation of DNA biosynthetic process	1	624.1×	0.004	NPPC

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NPRL2	0	0
NPR2	0	0
NPPC	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
NPR2	11	Binding:11

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NPR2	4.6.1.2	guanylate cyclase

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	1	NPR2
E	Difficult family or no structure, no drug	2	NPRL2, NPPC

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)
NPRL2	0	—
NPR2	11	—
NPPC	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.