hypospadias 2, X-linked

Summary

hypospadias 2, X-linked (MONDO:0010423) is a disease caused by MAMLD1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: MAMLD1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 16

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypospadias 2, X-linked
Mondo ID	MONDO:0010423
MeSH	C567462
OMIM	300758
UMLS	C2677879
MedGen	437064
GARD	0018186
Is cancer (heuristic)	no

Also known as: hypospadias 2, X-linked · hypospadias 2, X-linked, X-linked recessive · HYSP2

Data availability: 16 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 › hypospadias › hypospadias 2, X-linked

Related subtypes (4): hypospadias 3, autosomal, hypospadias 1, X-linked, hypospadias 4, X-linked, isolated female hypospadias

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

16 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 4 pathogenic, 3 benign/likely benign, 2 benign, 2 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
11611	NM_005491.5(MAMLD1):c.589G>T (p.Glu197Ter)	MAMLD1	Pathogenic	no assertion criteria provided
11612	NM_005491.5(MAMLD1):c.808C>T (p.Gln270Ter)	MAMLD1	Pathogenic	no assertion criteria provided
11613	NM_005491.5(MAMLD1):c.2176C>T (p.Arg726Ter)	MAMLD1	Pathogenic	criteria provided, single submitter
431447	NM_005491.5(MAMLD1):c.394G>T (p.Glu132Ter)	MAMLD1	Pathogenic	criteria provided, single submitter
1685936	NM_005491.5(MAMLD1):c.1804C>A (p.Gln602Lys)	MAMLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2277722	NM_005491.5(MAMLD1):c.1868G>A (p.Arg623His)	MAMLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1805237	NM_005491.5(MAMLD1):c.*159T>C	MAMLD1	Uncertain significance	criteria provided, single submitter
2072761	NM_005491.5(MAMLD1):c.2144T>C (p.Leu715Pro)	MAMLD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3235051	NM_005491.5(MAMLD1):c.*900A>G	MAMLD1	Uncertain significance	criteria provided, single submitter
3377344	NM_005491.5(MAMLD1):c.1592C>T (p.Pro531Leu)	MAMLD1	Uncertain significance	criteria provided, single submitter
3382067	NM_005491.5(MAMLD1):c.1479_1487dup (p.Gln502_Ala503insGlnGlnGln)	MAMLD1	Uncertain significance	criteria provided, single submitter
1169167	NM_005491.5(MAMLD1):c.1699C>T (p.Pro567Ser)	MAMLD1	Benign	criteria provided, multiple submitters, no conflicts
1600911	NM_005491.5(MAMLD1):c.1291C>T (p.Leu431Phe)	MAMLD1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
724749	NM_005491.5(MAMLD1):c.2284+8A>T	MAMLD1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
804096	NM_005491.5(MAMLD1):c.1514T>C (p.Val505Ala)	MAMLD1	Benign	criteria provided, multiple submitters, no conflicts
982815	NM_005491.5(MAMLD1):c.*126C>T	MAMLD1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · 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
MAMLD1	Strong	X-linked	hypospadias 2, X-linked	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MAMLD1	Orphanet:456328	X-linked myotubular myopathy-abnormal genitalia syndrome
MAMLD1	Orphanet:95706	Non-syndromic posterior hypospadias

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
MAMLD1	HGNC:2568	ENSG00000013619	Q13495	Mastermind-like domain-containing protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MAMLD1	Mastermind-like domain-containing protein 1	Transactivates the HES3 promoter independently of NOTCH proteins.

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)
MAMLD1	Other/Unknown	no		MAMLD1

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
male germ line stem cell (sensu Vertebrata) in testis	1
right ovary	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MAMLD1	197	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, right ovary, right testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MAMLD1	1,220

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MAMLD1	Q13495	44.08

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 31. 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
NOTCH2 intracellular domain regulates transcription	1	951.7×	0.005	MAMLD1
RUNX3 regulates NOTCH signaling	1	815.7×	0.005	MAMLD1
Regulation of beta-cell development	1	713.8×	0.005	MAMLD1
Signaling by NOTCH2	1	713.8×	0.005	MAMLD1
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	1	713.8×	0.005	MAMLD1
NOTCH4 Intracellular Domain Regulates Transcription	1	571.0×	0.005	MAMLD1
Signaling by NOTCH3	1	519.1×	0.005	MAMLD1
Signaling by NOTCH4	1	496.5×	0.005	MAMLD1
NOTCH3 Intracellular Domain Regulates Transcription	1	439.2×	0.005	MAMLD1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1	407.9×	0.005	MAMLD1
Signaling by NOTCH1 in Cancer	1	407.9×	0.005	MAMLD1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1	407.9×	0.005	MAMLD1
Notch-HLH transcription pathway	1	407.9×	0.005	MAMLD1
Formation of paraxial mesoderm	1	407.9×	0.005	MAMLD1
Pre-NOTCH Expression and Processing	1	368.4×	0.005	MAMLD1
Signaling by NOTCH1	1	356.9×	0.005	MAMLD1
Transcriptional regulation by RUNX3	1	271.9×	0.007	MAMLD1
Gastrulation	1	259.6×	0.007	MAMLD1
NOTCH1 Intracellular Domain Regulates Transcription	1	237.9×	0.007	MAMLD1
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	196.9×	0.007	MAMLD1
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	196.9×	0.007	MAMLD1
Signaling by NOTCH	1	175.7×	0.008	MAMLD1
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	1	146.4×	0.009	MAMLD1
Pre-NOTCH Transcription and Translation	1	122.8×	0.011	MAMLD1
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.022	MAMLD1
RNA Polymerase II Transcription	1	22.5×	0.053	MAMLD1
Gene expression (Transcription)	1	17.8×	0.064	MAMLD1
Generic Transcription Pathway	1	15.1×	0.073	MAMLD1
Developmental Biology	1	14.5×	0.074	MAMLD1
Disease	1	13.1×	0.079	MAMLD1

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
spermatid differentiation	1	1685.2×	0.002	MAMLD1
male gonad development	1	156.0×	0.010	MAMLD1
regulation of transcription by RNA polymerase II	1	11.7×	0.086	MAMLD1

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
MAMLD1	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	MAMLD1

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)
MAMLD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.