Nephronophthisis 14

Summary

Nephronophthisis 14 (MONDO:0013916) is a disease caused by ZNF423 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: ZNF423 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 845

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	nephronophthisis 14
Mondo ID	MONDO:0013916
OMIM	614844
DOID	DOID:0111122
UMLS	C3539071
MedGen	761313
GARD	0024962
Is cancer (heuristic)	no

Also known as: nephronophthisis (disease) caused by mutation in ZNF423 · nephronophthisis 14 · nephronophthisis type 14 · NPHP14 · ZNF423 nephronophthisis (disease)

Data availability: 845 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › nephronophthisis › nephronophthisis 14

Related subtypes (17): nephronophthisis 1, nephronophthisis 2, nephronophthisis 3, nephronophthisis 4, nephronophthisis 7, nephronophthisis-like nephropathy 1, nephronophthisis 11, nephronophthisis 12, nephronophthisis 9, nephronophthisis 13, nephronophthisis 15, nephronophthisis 16, nephronophthisis 18, nephronophthisis 19, nephronophthisis 20, late-onset nephronophthisis, nephronophthisis-like nephropathy 2

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

600 retrieved; paginated sample, class counts are floors:

283 uncertain significance, 280 likely benign, 15 benign, 12 benign/likely benign, 10 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
2426048	NC_000016.9:g.(?49525186)(51631253_?)del	ADCY7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1034635	NM_001379286.1(ZNF423):c.146C>T (p.Ala49Val)	ZNF423	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1037033	NM_001379286.1(ZNF423):c.2268G>T (p.Lys756Asn)	ZNF423	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197817	NM_001379286.1(ZNF423):c.1655G>T (p.Gly552Val)	ZNF423	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197819	NM_001379286.1(ZNF423):c.2649C>T (p.Ser883=)	ZNF423	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197820	NM_001379286.1(ZNF423):c.807C>T (p.Asp269=)	ZNF423	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197823	NM_001379286.1(ZNF423):c.1168T>C (p.Ser390Pro)	ZNF423	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197824	NM_001379286.1(ZNF423):c.2400C>T (p.Thr800=)	ZNF423	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2438685	NM_001379286.1(ZNF423):c.2532G>A (p.Ala844=)	ZNF423	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286686	NM_001379286.1(ZNF423):c.819C>T (p.Cys273=)	ZNF423	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2426049	NC_000016.9:g.(?49525186)(51631253_?)dup	ADCY7	Uncertain significance	criteria provided, single submitter
1000141	NM_001379286.1(ZNF423):c.97G>A (p.Ala33Thr)	ZNF423	Uncertain significance	criteria provided, single submitter
1001017	NM_001379286.1(ZNF423):c.382G>A (p.Gly128Arg)	ZNF423	Uncertain significance	criteria provided, single submitter
1001232	NM_001379286.1(ZNF423):c.2151G>C (p.Lys717Asn)	ZNF423	Uncertain significance	criteria provided, single submitter
1004622	NM_001379286.1(ZNF423):c.88G>A (p.Val30Met)	ZNF423	Uncertain significance	criteria provided, single submitter
1007655	NM_001379286.1(ZNF423):c.1459G>A (p.Ala487Thr)	ZNF423	Uncertain significance	criteria provided, multiple submitters, no conflicts
1009015	NM_001379286.1(ZNF423):c.2753A>G (p.Asn918Ser)	ZNF423	Uncertain significance	criteria provided, multiple submitters, no conflicts
1009172	NM_001379286.1(ZNF423):c.3454C>T (p.Arg1152Cys)	ZNF423	Uncertain significance	criteria provided, single submitter
1009563	NM_001379286.1(ZNF423):c.1891A>C (p.Ser631Arg)	ZNF423	Uncertain significance	criteria provided, single submitter
1009813	NM_001379286.1(ZNF423):c.1253G>A (p.Ser418Asn)	ZNF423	Uncertain significance	criteria provided, multiple submitters, no conflicts
1010074	NM_001379286.1(ZNF423):c.3208A>G (p.Lys1070Glu)	ZNF423	Uncertain significance	criteria provided, single submitter
1010382	NM_001379286.1(ZNF423):c.2848G>C (p.Glu950Gln)	ZNF423	Uncertain significance	criteria provided, single submitter
1010566	NM_001379286.1(ZNF423):c.3286C>G (p.Pro1096Ala)	ZNF423	Uncertain significance	criteria provided, multiple submitters, no conflicts
1011162	NM_001379286.1(ZNF423):c.3463A>T (p.Thr1155Ser)	ZNF423	Uncertain significance	criteria provided, single submitter
1013786	NM_001379286.1(ZNF423):c.1817A>T (p.Lys606Met)	ZNF423	Uncertain significance	criteria provided, single submitter
1013846	NM_001379286.1(ZNF423):c.295C>G (p.Pro99Ala)	ZNF423	Uncertain significance	criteria provided, multiple submitters, no conflicts
1014219	NM_001379286.1(ZNF423):c.2882G>A (p.Arg961Gln)	ZNF423	Uncertain significance	criteria provided, multiple submitters, no conflicts
1015342	NM_001379286.1(ZNF423):c.2968A>G (p.Ser990Gly)	ZNF423	Uncertain significance	criteria provided, single submitter
1016552	NM_001379286.1(ZNF423):c.1646G>C (p.Cys549Ser)	ZNF423	Uncertain significance	criteria provided, single submitter
1017494	NM_001379286.1(ZNF423):c.3277A>G (p.Asn1093Asp)	ZNF423	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 8 · 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
ZNF423	Strong	Autosomal recessive	nephronophthisis 14	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ZNF423	Orphanet:2318	Joubert syndrome with oculorenal defect
ZNF423	Orphanet:93591	Infantile nephronophthisis
CFTR	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
CFTR	Orphanet:48	Congenital bilateral absence of vas deferens
CFTR	Orphanet:498359	Aquagenic palmoplantar keratoderma
CFTR	Orphanet:586	Cystic fibrosis
CFTR	Orphanet:60033	Idiopathic bronchiectasis
CFTR	Orphanet:700124	Autosomal recessive hereditary chronic pancreatitis

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
ZNF423	HGNC:16762	ENSG00000102935	Q2M1K9	Zinc finger protein 423	gencc,clinvar
CFTR	HGNC:1884	ENSG00000001626	P13569	Cystic fibrosis transmembrane conductance regulator	clinvar
ADCY7	HGNC:238	ENSG00000121281	P51828	Adenylate cyclase type 7	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZNF423	Zinc finger protein 423	Transcription factor that can both act as an activator or a repressor depending on the context.
CFTR	Cystic fibrosis transmembrane conductance regulator	Epithelial ion channel that plays an important role in the regulation of epithelial ion and water transport and fluid homeostasis.
ADCY7	Adenylate cyclase type 7	Adenylate cyclase that mediates formation of both cyclic AMP (cAMP) and cyclic di-AMP (c-di-AMP).

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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
Transporter	1	25.9×	0.114
Enzyme (other)	1	4.0×	0.321
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ZNF423	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf
CFTR	Transporter	yes	2.7.4.3	ABC_transporter-like_ATP-bd, AAA+_ATPase, CFTR/ABCC7
ADCY7	Enzyme (other)	yes	4.6.1.1	A/G_cyclase, Adcy_conserved_dom, A/G_cyclase_CS

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
biceps brachii	1
cartilage tissue	1
skeletal muscle tissue of biceps brachii	1
body of pancreas	1
gall bladder	1
pancreas	1
granulocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZNF423	252	broad	marker	skeletal muscle tissue of biceps brachii, biceps brachii, cartilage tissue
CFTR	193	broad	marker	body of pancreas, gall bladder, pancreas
ADCY7	271	ubiquitous	marker	granulocyte, monocyte, mononuclear cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CFTR	7,664
ZNF423	1,526
ADCY7	1,213

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CFTR	P13569	58
ZNF423	Q2M1K9	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADCY7	P51828	77.32

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 58. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RHO GTPases regulate CFTR trafficking	1	1268.9×	0.023	CFTR
Adenylate cyclase activating pathway	1	380.7×	0.023	ADCY7
Adenylate cyclase inhibitory pathway	1	253.8×	0.023	ADCY7
PKA activation in glucagon signalling	1	223.9×	0.023	ADCY7
PKA activation	1	211.5×	0.023	ADCY7
Activation of GABAB receptors	1	200.3×	0.023	ADCY7
PKA-mediated phosphorylation of CREB	1	190.3×	0.023	ADCY7
GABA B receptor activation	1	181.3×	0.023	ADCY7
Chaperone Mediated Autophagy	1	165.5×	0.023	CFTR
Anti-inflammatory response favouring Leishmania parasite infection	1	131.3×	0.023	ADCY7
Leishmania parasite growth and survival	1	131.3×	0.023	ADCY7
Calmodulin induced events	1	126.9×	0.023	ADCY7
CaM pathway	1	126.9×	0.023	ADCY7
Transcriptional regulation of brown and beige adipocyte differentiation by EBF2	1	126.9×	0.023	ZNF423
Ca-dependent events	1	122.8×	0.023	ADCY7
Aquaporin-mediated transport	1	122.8×	0.023	ADCY7
Glucagon signaling in metabolic regulation	1	115.3×	0.023	ADCY7
G-protein mediated events	1	108.8×	0.023	ADCY7
Late endosomal microautophagy	1	108.8×	0.023	CFTR
DAG and IP3 signaling	1	105.7×	0.023	ADCY7
GABA receptor activation	1	105.7×	0.023	ADCY7
Response of endothelial cells to shear stress	1	100.2×	0.023	ADCY7
FCGR3A-mediated IL10 synthesis	1	97.6×	0.023	ADCY7
Opioid Signalling	1	88.5×	0.023	ADCY7
PLC beta mediated events	1	88.5×	0.023	ADCY7
Vasopressin regulates renal water homeostasis via Aquaporins	1	88.5×	0.023	ADCY7
Cellular responses to mechanical stimuli	1	86.5×	0.023	ADCY7
ADORA2B mediated anti-inflammatory cytokines production	1	84.6×	0.023	ADCY7
GPER1 signaling	1	82.8×	0.023	ADCY7
Aggrephagy	1	82.8×	0.023	CFTR

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
intracellular pH elevation	1	1872.4×	0.009	CFTR
transepithelial water transport	1	1123.5×	0.009	CFTR
positive regulation of enamel mineralization	1	1123.5×	0.009	CFTR
regulation of adaptive immune response	1	624.1×	0.009	ADCY7
membrane hyperpolarization	1	624.1×	0.009	CFTR
multicellular organismal-level water homeostasis	1	561.7×	0.009	CFTR
cAMP biosynthetic process	1	468.1×	0.009	ADCY7
amelogenesis	1	468.1×	0.009	CFTR
cellular response to lithium ion	1	374.5×	0.009	ADCY7
cellular response to forskolin	1	374.5×	0.009	CFTR
cellular response to ethanol	1	351.1×	0.009	ADCY7
water transport	1	330.4×	0.009	CFTR
maternal process involved in female pregnancy	1	312.1×	0.009	ADCY7
cellular response to glucagon stimulus	1	280.9×	0.009	ADCY7
bicarbonate transport	1	267.5×	0.009	CFTR
cholesterol transport	1	244.2×	0.009	CFTR
vascular endothelial cell response to laminar fluid shear stress	1	244.2×	0.009	ADCY7
sperm capacitation	1	224.7×	0.009	CFTR
renal water homeostasis	1	170.2×	0.011	ADCY7
positive regulation of BMP signaling pathway	1	151.8×	0.012	ZNF423
cholesterol biosynthetic process	1	140.4×	0.012	CFTR
negative regulation of cytokine production involved in inflammatory response	1	140.4×	0.012	ADCY7
protein localization to cilium	1	133.8×	0.012	ZNF423
negative regulation of cold-induced thermogenesis	1	114.6×	0.013	ZNF423
cellular response to cAMP	1	96.8×	0.015	CFTR
chloride transmembrane transport	1	79.1×	0.018	CFTR
transmembrane transport	1	56.2×	0.024	CFTR
response to endoplasmic reticulum stress	1	55.6×	0.024	CFTR
establishment of localization in cell	1	53.5×	0.024	CFTR
Notch signaling pathway	1	47.2×	0.026	ZNF423

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CFTR	IVACAFTOR

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CFTR	14	4
ZNF423	0	0
ADCY7	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IVACAFTOR	4	CFTR
LUMACAFTOR	4	CFTR
TEZACAFTOR	4	CFTR
ELEXACAFTOR	4	CFTR
GLYBURIDE	4	CFTR
RUTIN	3	CFTR
BAMOCAFTOR	3	CFTR
QUERCETIN	3	CFTR
GALICAFTOR	2	CFTR
GENISTEIN	2	CFTR
ICENTICAFTOR	2	CFTR
NAVOCAFTOR	2	CFTR
RISELCAFTOR	2	CFTR
GLPG-2737	2	CFTR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CFTR	520	Binding:497, Functional:17, ADMET:5, Toxicity:1
ADCY7	16	Binding:14, Functional:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CFTR	2.7.4.3, 5.6.1.6	adenylate kinase, channel-conductance-controlling ATPase
ADCY7	4.6.1.1	adenylate cyclase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CFTR	520

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
CFTR	1

Chemical tractability of cohort targets

14 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.

Compound	Max phase	Cohort target (bioactivity)
IVACAFTOR	4	CFTR
LUMACAFTOR	4	CFTR
TEZACAFTOR	4	CFTR
ELEXACAFTOR	4	CFTR
GLYBURIDE	4	CFTR
RUTIN	3	CFTR
BAMOCAFTOR	3	CFTR
QUERCETIN	3	CFTR
GALICAFTOR	2	CFTR
GENISTEIN	2	CFTR
ICENTICAFTOR	2	CFTR
NAVOCAFTOR	2	CFTR
RISELCAFTOR	2	CFTR
GLPG-2737	2	CFTR

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CFTR
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ADCY7
E	Difficult family or no structure, no drug	1	ZNF423

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)
ZNF423	0	—
ADCY7	16	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.