Noonan syndrome 14

Summary

Noonan syndrome 14 (MONDO:0030679) is a disease caused by SPRED2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: SPRED2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Noonan syndrome 14
Mondo ID	MONDO:0030679
OMIM	619745
UMLS	C5676916
MedGen	1807988
GARD	0025608
Is cancer (heuristic)	no

Also known as: Noonan syndrome 14 · NS14

Data availability: 5 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Noonan syndrome › Noonan syndrome 14

Related subtypes (13): Noonan syndrome 1, Noonan syndrome 2, Noonan syndrome 3, Noonan syndrome 4, Noonan syndrome 5, Noonan syndrome 6, Noonan syndrome 7, Noonan syndrome 8, Noonan syndrome 9, Noonan syndrome 10, Noonan syndrome 11, noonan syndrome 12, Noonan syndrome 13

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

5 retrieved; paginated sample, class counts are floors:

3 pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1209657	NM_181784.3(SPRED2):c.1142_1143del (p.Leu381fs)	SPRED2	Pathogenic	criteria provided, single submitter
1209658	NM_181784.3(SPRED2):c.299T>C (p.Leu100Pro)	SPRED2	Pathogenic	criteria provided, single submitter
1210167	NM_181784.3(SPRED2):c.187C>T (p.Arg63Ter)	SPRED2	Pathogenic	no assertion criteria provided
3362677	NM_181784.3(SPRED2):c.89G>A (p.Trp30Ter)	SPRED2	Likely pathogenic	criteria provided, single submitter
4849286	NM_181784.3(SPRED2):c.125_146dup (p.Pro49_Glu50insGlyLeuTer)	SPRED2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
SPRED2	Strong	Autosomal recessive	Noonan syndrome 14	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SPRED2	Orphanet:648	Noonan syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SPRED2	HGNC:17722	ENSG00000198369	Q7Z698	Sprouty-related, EVH1 domain-containing protein 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SPRED2	Sprouty-related, EVH1 domain-containing protein 2	Negatively regulates Ras signaling pathways and downstream activation of MAP kinases.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SPRED2	Other/Unknown	no		WH1/EVH1_dom, Sprouty, PH-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of sigmoid colon	1
sural nerve	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SPRED2	270	ubiquitous	marker	sural nerve, mucosa of sigmoid colon, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SPRED2	1,283

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SPRED2	Q7Z698	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RAS signaling downstream of NF1 loss-of-function variants	1	1631.4×	0.005	SPRED2
FGFRL1 modulation of FGFR1 signaling	1	878.5×	0.005	SPRED2
Signaling by FGFR1	1	815.7×	0.005	SPRED2
Signaling by FGFR	1	346.1×	0.009	SPRED2
Oncogenic MAPK signaling	1	248.3×	0.010	SPRED2
Regulation of RAS by GAPs	1	193.6×	0.011	SPRED2
MAPK1/MAPK3 signaling	1	131.3×	0.014	SPRED2
MAPK family signaling cascades	1	102.9×	0.016	SPRED2
RAF/MAP kinase cascade	1	61.1×	0.023	SPRED2
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.023	SPRED2
Signaling by Receptor Tyrosine Kinases	1	51.7×	0.023	SPRED2
Disease	1	13.1×	0.083	SPRED2
Signal Transduction	1	10.2×	0.098	SPRED2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of lens fiber cell differentiation	1	2808.7×	0.002	SPRED2
negative regulation of intracellular signal transduction	1	2106.5×	0.002	SPRED2
positive regulation of DNA damage response, signal transduction by p53 class mediator	1	991.3×	0.002	SPRED2
negative regulation of epithelial to mesenchymal transition	1	411.0×	0.004	SPRED2
negative regulation of MAPK cascade	1	300.9×	0.005	SPRED2
negative regulation of ERK1 and ERK2 cascade	1	216.1×	0.005	SPRED2
negative regulation of transforming growth factor beta receptor signaling pathway	1	173.7×	0.006	SPRED2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SPRED2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
E	Difficult family or no structure, no drug	1	SPRED2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SPRED2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.