Pituitary hormone deficiency, combined, 2

Summary

Pituitary hormone deficiency, combined, 2 (MONDO:0009878) is a disease caused by PROP1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: PROP1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 153

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pituitary hormone deficiency, combined, 2
Mondo ID	MONDO:0009878
MeSH	C563172
OMIM	262600
DOID	DOID:0061020
UMLS	C0878683
MedGen	209236
GARD	0015222
Is cancer (heuristic)	no

Also known as: combined pituitary hormone deficiencies, genetic form caused by mutation in PROP1 · CPHD2 · pituitary hormone deficiency, combined, 2 · pituitary hormone deficiency, combined, type 2 · PROP1 combined pituitary hormone deficiencies, genetic form

Data availability: 153 ClinVar variants · 5 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 › panhypopituitarism › pituitary hormone deficiency, combined, 2

Related subtypes (1): panhypopituitarism, X-linked

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

153 retrieved; paginated sample, class counts are floors:

52 likely pathogenic, 30 uncertain significance, 17 pathogenic/likely pathogenic, 17 conflicting classifications of pathogenicity, 14 pathogenic, 12 likely benign, 10 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
576	NM_000277.3(PAH):c.1315+1G>A	PAH	Pathogenic	reviewed by expert panel
1070901	NM_006261.5(PROP1):c.63del (p.Leu22fs)	PROP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1071125	NM_006261.5(PROP1):c.129dup (p.Arg44fs)	PROP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188982	NM_006261.5(PROP1):c.334C>T (p.Arg112Ter)	PROP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189062	NM_006261.5(PROP1):c.310del (p.Arg104fs)	PROP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2023152	NM_006261.5(PROP1):c.95del (p.Pro32fs)	PROP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2678070	NM_006261.5(PROP1):c.211C>T (p.Arg71Cys)	PROP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2678071	NM_006261.5(PROP1):c.109+1G>A	PROP1	Pathogenic	criteria provided, multiple submitters, no conflicts
36702	NM_006261.5(PROP1):c.46C>T (p.Arg16Ter)	PROP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371125	NM_006261.5(PROP1):c.390_391del (p.Leu131fs)	PROP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
371145	NM_006261.5(PROP1):c.343-2A>T	PROP1	Pathogenic	criteria provided, single submitter
371561	NM_006261.5(PROP1):c.557del (p.Ala186fs)	PROP1	Pathogenic	criteria provided, single submitter
551288	NM_006261.5(PROP1):c.2T>C (p.Met1Thr)	PROP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
552692	NM_006261.5(PROP1):c.373C>T (p.Arg125Trp)	PROP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
557212	NM_006261.5(PROP1):c.156dup (p.Arg53fs)	PROP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
557236	NM_006261.5(PROP1):c.386_387dup (p.Ser130fs)	PROP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
557723	NM_006261.5(PROP1):c.74_75dup (p.His26fs)	PROP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
558722	NM_006261.5(PROP1):c.340C>T (p.Gln114Ter)	PROP1	Pathogenic	criteria provided, single submitter
631963	NM_006261.5(PROP1):c.109+1G>T	PROP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8095	NM_006261.5(PROP1):c.358C>T (p.Arg120Cys)	PROP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8096	NM_006261.5(PROP1):c.349T>A (p.Phe117Ile)	PROP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8097	NM_006261.5(PROP1):c.150_151del (p.Gly52fs)	PROP1	Pathogenic	no assertion criteria provided
8098	NM_006261.5(PROP1):c.301_302del (p.Leu102fs)	PROP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8100	NM_006261.5(PROP1):c.263T>C (p.Phe88Ser)	PROP1	Pathogenic	no assertion criteria provided
8101	NM_006261.5(PROP1):c.112_124del (p.Ser38fs)	PROP1	Pathogenic	criteria provided, multiple submitters, no conflicts
8102	NM_006261.5(PROP1):c.150del (p.Arg53fs)	PROP1	Pathogenic	criteria provided, multiple submitters, no conflicts
8103	NM_006261.5(PROP1):c.218G>A (p.Arg73His)	PROP1	Pathogenic	criteria provided, multiple submitters, no conflicts
8104	NM_006261.5(PROP1):c.217C>T (p.Arg73Cys)	PROP1	Pathogenic	criteria provided, multiple submitters, no conflicts
8105	NM_006261.5(PROP1):c.295C>T (p.Arg99Ter)	PROP1	Pathogenic	criteria provided, multiple submitters, no conflicts
8106	NM_006261.5(PROP1):c.296G>A (p.Arg99Gln)	PROP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 6 · 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
PROP1	Definitive	Autosomal recessive	pituitary hormone deficiency, combined, 2	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PROP1	Orphanet:226307	Hypothyroidism due to deficient transcription factors involved in pituitary development or function
PROP1	Orphanet:90695	Non-acquired panhypopituitarism
PROP1	Orphanet:95494	Combined pituitary hormone deficiencies, genetic forms
PAH	Orphanet:2209	Maternal phenylketonuria syndrome
PAH	Orphanet:293284	Tetrahydrobiopterin-responsive phenylketonuria
PAH	Orphanet:708895	Tetrahydrobiopterin-unresponsive phenylketonuria

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PROP1	HGNC:9455	ENSG00000175325	O75360	Homeobox protein prophet of Pit-1	gencc,clinvar
PAH	HGNC:8582	ENSG00000171759	P00439	Phenylalanine-4-hydroxylase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PROP1	Homeobox protein prophet of Pit-1	Possibly involved in the ontogenesis of pituitary gonadotropes, as well as somatotropes, lactotropes and caudomedial thyrotropes.
PAH	Phenylalanine-4-hydroxylase	Catalyzes the hydroxylation of L-phenylalanine to L-tyrosine.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.228
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PROP1	Transcription factor	no		HTH_motif, HD, Homeodomain-like_sf
PAH	Enzyme (other)	yes	1.14.16.1	ArAA_hydroxylase, ACT_dom, Phe-4-hydroxylase_tetra

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)	1
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	1
bone marrow cell	1
pituitary gland	1
gall bladder	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PROP1	4		yes	pituitary gland, adenohypophysis, bone marrow cell
PAH	175	broad	marker	right lobe of liver, liver, gall bladder

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PAH	1,953
PROP1	1,160

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PAH	P00439	20

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PROP1	O75360	70.74

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 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
Phenylketonuria	1	11420.0×	2e-04	PAH
Phenylalanine metabolism	1	1903.3×	5e-04	PAH

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
L-tyrosine biosynthetic process	1	8426.0×	8e-04	PAH
amino acid biosynthetic process	1	8426.0×	8e-04	PAH
hypophysis morphogenesis	1	4213.0×	0.001	PROP1
catecholamine biosynthetic process	1	2808.7×	0.001	PAH
somatotropin secreting cell differentiation	1	2106.5×	0.001	PROP1
hypothalamus cell differentiation	1	1685.2×	0.001	PROP1
L-phenylalanine catabolic process	1	1053.2×	0.002	PAH
dorsal/ventral pattern formation	1	210.7×	0.008	PROP1
blood vessel development	1	187.2×	0.008	PROP1
central nervous system development	1	57.7×	0.024	PROP1
cell migration	1	30.8×	0.041	PROP1
negative regulation of apoptotic process	1	17.4×	0.066	PROP1
apoptotic process	1	14.3×	0.074	PROP1
regulation of transcription by RNA polymerase II	1	5.8×	0.164	PROP1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PROP1	0	0
PAH	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
PAH	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PAH	1.14.16.1	phenylalanine 4-monooxygenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	1	PAH
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PROP1

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)
PROP1	0	—
PAH	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.