Male infertility with teratozoospermia due to single gene mutation

Summary

Male infertility with teratozoospermia due to single gene mutation (MONDO:0018394) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 9
• Phenotypes (HPO): 8

Clinical features

Signs & symptoms

Clinical features (HPO)

8 HPO clinical features (Orphanet curated; top 8 by frequency):

HPO ID	Term	Frequency
HP:0000118	Phenotypic abnormality	Very frequent (80-99%)
HP:0000837	Increased circulating gonadotropin level	Very frequent (80-99%)
HP:0008669	Abnormal spermatogenesis	Very frequent (80-99%)
HP:0008734	Decreased testicular size	Very frequent (80-99%)
HP:0011961	Non-obstructive azoospermia	Very frequent (80-99%)
HP:0012205	Globozoospermia	Very frequent (80-99%)
HP:0012864	Abnormal sperm morphology	Very frequent (80-99%)
HP:0012868	Sperm tail anomaly	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	male infertility with teratozoospermia due to single gene mutation
Mondo ID	MONDO:0018394
Orphanet	399808
SNOMED CT	764096006
UMLS	C4706677
MedGen	1643966
GARD	0017654
Is cancer (heuristic)	no

Data availability: 9 ClinVar variants.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › reproductive system disorder › male reproductive system disorder › male infertility › male infertility with teratozoospermia due to single gene mutation

Related subtypes (7): infertility due to extratesticular cause, oligospermia, spermatogenic failure, partial chromosome Y deletion, male infertility due to acephalic spermatozoa, azoospermia, oligoasthenoteratozoospermia

Subtypes (3): spermatogenic failure 5, spermatogenic failure 12, male infertility due to globozoospermia

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:

7 pathogenic, 1 pathogenic/likely pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
617790	NM_032131.6(ARMC2):c.1023+1G>A	ARMC2	Pathogenic	no assertion criteria provided
627628	NM_032131.6(ARMC2):c.2279T>A (p.Ile760Asn)	ARMC2	Pathogenic	no assertion criteria provided
627629	NM_032131.6(ARMC2):c.2353_2354del (p.Leu785fs)	ARMC2	Pathogenic	no assertion criteria provided
627630	NM_032131.6(ARMC2):c.1284_1288del (p.Lys428fs)	ARMC2	Pathogenic	no assertion criteria provided
627631	NM_032131.6(ARMC2):c.421C>T (p.Gln141Ter)	ARMC2	Pathogenic	no assertion criteria provided
548449	NM_144668.6(CFAP251):c.331G>T (p.Glu111Ter)	CFAP251	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
548450	NM_144668.6(CFAP251):c.123del (p.Asp42fs)	CFAP251	Pathogenic	no assertion criteria provided
812095	NM_033364.4(CFAP91):c.682+1G>A	CFAP91	Pathogenic	no assertion criteria provided
812096	NM_033364.4(CFAP91):c.124G>C (p.Asp42His)	CFAP91	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ARMC2	Orphanet:276234	Non-syndromic male infertility due to sperm motility disorder
CFAP251	Orphanet:276234	Non-syndromic male infertility due to sperm motility disorder

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
ARMC2	HGNC:23045	ENSG00000118690	Q8NEN0	Armadillo repeat-containing protein 2	clinvar
CFAP91	HGNC:24010	ENSG00000183833	Q7Z4T9	Cilia- and flagella-associated protein 91	clinvar
CFAP251	HGNC:28506	ENSG00000158023	Q8TBY9	Cilia- and flagella-associated protein 251	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ARMC2	Armadillo repeat-containing protein 2	Required for sperm flagellum axoneme organization and function.
CFAP91	Cilia- and flagella-associated protein 91	Involved in sperm flagellum axonemal organization and function.
CFAP251	Cilia- and flagella-associated protein 251	Involved in spermatozoa motility.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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
Scaffold/PPI	1	5.8×	0.327
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ARMC2	Other/Unknown	no		Armadillo, ARM-like, ARM-type_fold
CFAP91	Other/Unknown	no		CFAP91, CFAP91_dom
CFAP251	Scaffold/PPI	no		WD40_rpt, Quinoprotein_ADH-like_sf, EF-hand-dom_pair

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
right uterine tube	3
bronchial epithelial cell	2
bronchus	2
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ARMC2	173	ubiquitous	marker	oocyte, right uterine tube, secondary oocyte
CFAP91	212	broad	marker	right uterine tube, bronchial epithelial cell, bronchus
CFAP251	177	broad	marker	right uterine tube, bronchial epithelial cell, bronchus

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CFAP251	1,050
CFAP91	757
ARMC2	614

Intra-cohort edges

A	B	Sources
ARMC2	CFAP251	string_interaction
ARMC2	CFAP91	string_interaction
CFAP251	CFAP91	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CFAP91	Q7Z4T9	1
CFAP251	Q8TBY9	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARMC2	Q8NEN0	75.57

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 3 evidence-associated genes (0 with Reactome annotation).

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
cilium movement	2	261.3×	2e-04	CFAP91, CFAP251
axonemal central apparatus assembly	1	936.2×	0.005	CFAP91
cilium organization	1	200.6×	0.012	ARMC2
nucleus organization	1	187.2×	0.012	ARMC2
sperm axoneme assembly	1	156.0×	0.012	ARMC2
cell morphogenesis	1	52.5×	0.028	ARMC2
flagellated sperm motility	1	39.0×	0.033	CFAP251
spermatogenesis	1	11.7×	0.093	CFAP91
cell differentiation	1	9.7×	0.100	CFAP91

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
ARMC2	0	0
CFAP91	0	0
CFAP251	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
E	Difficult family or no structure, no drug	3	ARMC2, CFAP91, CFAP251

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)
ARMC2	0	—
CFAP91	0	—
CFAP251	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.