Short stature due to growth hormone qualitative anomaly

Summary

Short stature due to growth hormone qualitative anomaly (MONDO:0009879) is a disease caused by GH1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GH1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 9

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	short stature due to growth hormone qualitative anomaly
Mondo ID	MONDO:0009879
MeSH	C537505
OMIM	262650
Orphanet	629
ICD-11	1665498704
UMLS	C1849779
MedGen	340412
GARD	0000408
Is cancer (heuristic)	no

Also known as: Kowarski syndrome

Data availability: 9 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › combined pituitary hormone deficiencies, genetic form › isolated congenital growth hormone deficiency › short stature due to growth hormone qualitative anomaly

Related subtypes (6): isolated growth hormone deficiency type II, isolated growth hormone deficiency type IA, isolated growth hormone deficiency type III, isolated growth hormone deficiency type IB, isolated growth hormone deficiency, type 4, isolated growth hormone deficiency, type 5

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:

4 pathogenic, 3 uncertain significance, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
15969	NM_000515.5(GH1):c.307C>T (p.Arg103Cys)	GH-LCR	Pathogenic	no assertion criteria provided
15970	NM_000515.5(GH1):c.291+1G>A	GH-LCR	Pathogenic	criteria provided, multiple submitters, no conflicts
15974	NM_000515.5(GH1):c.413A>G (p.Asp138Gly)	GH-LCR	Pathogenic	no assertion criteria provided
15981	NM_000515.5(GH1):c.236G>C (p.Cys79Ser)	GH-LCR	Pathogenic	no assertion criteria provided
3582621	NM_000515.5(GH1):c.595G>C (p.Val199Leu)	GH-LCR	Uncertain significance	criteria provided, single submitter
892518	NM_000515.5(GH1):c.350A>G (p.Gln117Arg)	GH-LCR	Uncertain significance	criteria provided, multiple submitters, no conflicts
3582622	NM_000515.5(GH1):c.346G>A (p.Val116Met)	GH1	Uncertain significance	criteria provided, single submitter
1635025	NM_000515.5(GH1):c.456+19G>T	GH-LCR	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
284727	NM_000515.5(GH1):c.116C>T (p.Ala39Val)	GH-LCR	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 4 · 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
GH1	Definitive	Autosomal recessive	isolated growth hormone deficiency type IA	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GH1	Orphanet:231662	Isolated growth hormone deficiency type IA
GH1	Orphanet:231671	Isolated growth hormone deficiency type IB
GH1	Orphanet:231679	Isolated growth hormone deficiency type II
GH1	Orphanet:629	Short stature due to growth hormone qualitative anomaly

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
GH1	HGNC:4261	ENSG00000259384	P01241	Somatotropin	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GH1	Somatotropin	Plays an important role in growth control.

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)
GH1	Other/Unknown	no		Somatotropin/Prolactin, 4_helix_cytokine-like_core, Somatotropin_CS

Expression context

Cohort genes with no expression data: 0.

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
adenohypophysis	1
male germ line stem cell (sensu Vertebrata) in testis	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GH1	119	tissue_specific	yes	pituitary gland, adenohypophysis, 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
GH1	1,007

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GH1	P01241	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Prolactin receptor signaling	1	761.3×	0.005	GH1
Synthesis, secretion, and deacylation of Ghrelin	1	601.0×	0.005	GH1
Growth hormone receptor signaling	1	475.8×	0.005	GH1
Peptide hormone metabolism	1	271.9×	0.006	GH1
Cytokine Signaling in Immune system	1	40.8×	0.034	GH1
Immune System	1	13.0×	0.081	GH1
Metabolism of proteins	1	12.4×	0.081	GH1

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
bone maturation	1	5617.3×	0.002	GH1
positive regulation of D-glucose transmembrane transport	1	2106.5×	0.002	GH1
growth hormone receptor signaling pathway via JAK-STAT	1	1532.0×	0.002	GH1
positive regulation of insulin-like growth factor receptor signaling pathway	1	1203.7×	0.002	GH1
growth hormone receptor signaling pathway	1	1203.7×	0.002	GH1
animal organ development	1	732.7×	0.003	GH1
cell surface receptor signaling pathway via STAT	1	561.7×	0.004	GH1
positive regulation of multicellular organism growth	1	495.6×	0.004	GH1
positive regulation of receptor signaling pathway via JAK-STAT	1	432.1×	0.004	GH1
response to nutrient levels	1	366.4×	0.004	GH1
cell surface receptor signaling pathway via JAK-STAT	1	290.6×	0.005	GH1
response to estradiol	1	198.3×	0.006	GH1
cytokine-mediated signaling pathway	1	130.6×	0.009	GH1
positive regulation of MAPK cascade	1	80.6×	0.013	GH1
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	78.4×	0.013	GH1

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
GH1	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	GH1

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)
GH1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.