Short-rib thoracic dysplasia 6 with or without polydactyly

Summary

Short-rib thoracic dysplasia 6 with or without polydactyly (MONDO:0009894) is a disease caused by NEK1 (GenCC Definitive), with 13 cohort genes. The dominant Reactome pathway is Intraflagellar transport (8 cohort genes).

At a glance

• Causal gene: NEK1 (GenCC Definitive)
• Cohort genes: 13
• ClinVar variants: 778

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	short-rib thoracic dysplasia 6 with or without polydactyly
Mondo ID	MONDO:0009894
OMIM	263520
DOID	DOID:0110092
NCIT	C122654
UMLS	C0024507
MedGen	44252
GARD	0015224
Is cancer (heuristic)	no

Also known as: Majewski syndrome · polydactyly with neonatal chondrodystrophy type II · short rib-polydactyly syndrome type II · short-rib thoracic dysplasia 6 with or without polydactyly · SRPS2A · SRTD6

Data availability: 778 ClinVar variants · 3 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › ciliopathy › Jeune syndrome › short-rib thoracic dysplasia 6 with or without polydactyly

Related subtypes (23): asphyxiating thoracic dystrophy 1, Ellis-van Creveld syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, Beemer-Langer syndrome, asphyxiating thoracic dystrophy 2, asphyxiating thoracic dystrophy 3, asphyxiating thoracic dystrophy 4, short-rib thoracic dysplasia 7 with or without polydactyly, asphyxiating thoracic dystrophy 5, short-rib thoracic dysplasia 8 with or without polydactyly, short-rib thoracic dysplasia 10 with or without polydactyly, short-rib thoracic dysplasia 11 with or without polydactyly, short-rib thoracic dysplasia 13 with or without polydactyly, short-rib thoracic dysplasia 14 with polydactyly, short-rib thoracic dysplasia 15 with polydactyly, short-rib thoracic dysplasia 16 with or without polydactyly, short-rib thoracic dysplasia 21 without polydactyly, short-rib thoracic dysplasia 19 with or without polydactyly, short-rib thoracic dysplasia 18 with polydactyly, short-rib thoracic dysplasia 20 with polydactyly, short-rib thoracic dysplasia 17 with or without polydactyly, Jeune syndrome - GRK2-related, short-rib thoracic dysplasia 22 without polydactyly

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:

267 uncertain significance, 172 likely benign, 52 conflicting classifications of pathogenicity, 38 pathogenic, 25 likely pathogenic, 24 benign, 16 pathogenic/likely pathogenic, 4 benign/likely benign, 2 pathogenic; other

ClinVar	Variant (HGVS)	Gene	Classification	Review
1802174	NM_001199397.3(NEK1):c.[1226G>A];[1948del]		Pathogenic	criteria provided, single submitter
369661	NM_001377.3(DYNC2H1):c.10322T>C (p.Leu3441Pro)	DYNC2H1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
446536	NM_001377.3(DYNC2H1):c.10042+2T>G	DYNC2H1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
446661	NM_153717.3(EVC):c.901AAG[1] (p.Lys302del)	EVC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
446662	NM_153717.3(EVC):c.363C>A (p.Tyr121Ter)	EVC	Pathogenic	criteria provided, multiple submitters, no conflicts
3383	NM_147127.5(EVC2):c.1195C>T (p.Arg399Ter)	EVC2	Pathogenic	criteria provided, multiple submitters, no conflicts
446664	NM_147127.5(EVC2):c.1708C>T (p.Gln570Ter)	EVC2	Pathogenic	criteria provided, multiple submitters, no conflicts
446675	NM_025129.5(FUZ):c.98_111+9del	FUZ	Pathogenic/Likely pathogenic	no assertion criteria provided
446697	NM_015662.3(IFT172):c.2765dup (p.Tyr922Ter)	IFT172	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
446655	NM_015650.4(IFT54):c.169G>A (p.Glu57Lys)	IFT54	Pathogenic/Likely pathogenic	no assertion criteria provided
1323355	NM_001199397.3(NEK1):c.2089C>T (p.Gln697Ter)	NEK1	Pathogenic	criteria provided, single submitter
1332832	NM_001199397.3(NEK1):c.1957C>T (p.Arg653Ter)	NEK1	Pathogenic	criteria provided, multiple submitters, no conflicts
1338755	NM_001199397.3(NEK1):c.213del (p.Glu72fs)	NEK1	Pathogenic	no assertion criteria provided
1380607	NM_001199397.3(NEK1):c.2991_2992insG (p.Ser998fs)	NEK1	Pathogenic	criteria provided, single submitter
1385116	NM_001199397.3(NEK1):c.2972_2973del (p.Ile991fs)	NEK1	Pathogenic	criteria provided, single submitter
1418443	NM_001199397.3(NEK1):c.1984dup (p.Glu662fs)	NEK1	Pathogenic	criteria provided, single submitter
1453965	NM_001199397.3(NEK1):c.1129C>T (p.Gln377Ter)	NEK1	Pathogenic	criteria provided, single submitter
1455845	NM_001199397.3(NEK1):c.934del (p.Ala312fs)	NEK1	Pathogenic	criteria provided, single submitter
1458767	NM_001199397.3(NEK1):c.602del (p.His201fs)	NEK1	Pathogenic	criteria provided, single submitter
1526104	NM_001199397.3(NEK1):c.3191C>G (p.Ser1064Ter)	NEK1	Pathogenic	criteria provided, single submitter
1698378	NM_001199397.3(NEK1):c.984del (p.Lys328fs)	NEK1	Pathogenic	criteria provided, single submitter
1898292	NM_001199397.3(NEK1):c.1606G>T (p.Glu536Ter)	NEK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191325	NM_001199397.3(NEK1):c.1690_1691del (p.Met564fs)	NEK1	Pathogenic	criteria provided, single submitter
193892	NM_001199397.3(NEK1):c.869-1G>T	NEK1	Pathogenic	criteria provided, multiple submitters, no conflicts
195286	NM_001199397.3(NEK1):c.117+1G>A	NEK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208600	NM_001199397.3(NEK1):c.3107C>G (p.Ser1036Ter)	NEK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2108520	NM_001199397.3(NEK1):c.1177C>T (p.Gln393Ter)	NEK1	Pathogenic	criteria provided, single submitter
2127401	NM_001199397.3(NEK1):c.3581C>A (p.Ser1194Ter)	NEK1	Pathogenic	criteria provided, single submitter
266055	NM_001199397.3(NEK1):c.214+1G>A	NEK1	Pathogenic; other	criteria provided, multiple submitters, no conflicts
266058	NM_001199397.3(NEK1):c.481C>T (p.Arg161Ter)	NEK1	Pathogenic; other	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 33 · 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
NEK1	Definitive	Autosomal recessive	short-rib thoracic dysplasia 6 with or without polydactyly	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NEK1	Orphanet:2751	Orofaciodigital syndrome type 2
NEK1	Orphanet:803	Amyotrophic lateral sclerosis
NEK1	Orphanet:93269	Short rib-polydactyly syndrome, Majewski type
PALLD	Orphanet:1333	Familial pancreatic carcinoma
IFT54	Orphanet:3156	Senior-Loken syndrome
IFT54	Orphanet:93269	Short rib-polydactyly syndrome, Majewski type
EVC2	Orphanet:289	Ellis Van Creveld syndrome
EVC2	Orphanet:952	Acrofacial dysostosis, Weyers type
IFT74	Orphanet:110	Bardet-Biedl syndrome
IFT74	Orphanet:137893	Male infertility due to large-headed multiflagellar polyploid spermatozoa
IFT74	Orphanet:475	Isolated Joubert syndrome
DYNC2LI1	Orphanet:289	Ellis Van Creveld syndrome
DYNC2LI1	Orphanet:474	Jeune syndrome
TTC21B	Orphanet:474	Jeune syndrome
TTC21B	Orphanet:93591	Infantile nephronophthisis
FUZ	Orphanet:3027	Caudal regression syndrome
FUZ	Orphanet:620158	Non-syndromic non-specific multisutural craniosynostosis
WDR35	Orphanet:1515	Cranioectodermal dysplasia
WDR35	Orphanet:498497	Short rib-polydactyly syndrome type 5
WDR35	Orphanet:93271	Short rib-polydactyly syndrome, Verma-Naumoff type
IFT80	Orphanet:474	Jeune syndrome
IFT80	Orphanet:93268	Short rib-polydactyly syndrome, Beemer-Langer type
IFT80	Orphanet:93271	Short rib-polydactyly syndrome, Verma-Naumoff type
DYNC2H1	Orphanet:474	Jeune syndrome
DYNC2H1	Orphanet:93269	Short rib-polydactyly syndrome, Majewski type
DYNC2H1	Orphanet:93270	Short rib-polydactyly syndrome, Saldino-Noonan type
DYNC2H1	Orphanet:93271	Short rib-polydactyly syndrome, Verma-Naumoff type
IFT172	Orphanet:110	Bardet-Biedl syndrome
IFT172	Orphanet:140969	Saldino-Mainzer syndrome
IFT172	Orphanet:474	Jeune syndrome
IFT172	Orphanet:791	Retinitis pigmentosa
EVC	Orphanet:289	Ellis Van Creveld syndrome
EVC	Orphanet:952	Acrofacial dysostosis, Weyers type

Cohort genes → proteins

13 cohort genes, 13 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	13

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NEK1	HGNC:7744	ENSG00000137601	Q96PY6	Serine/threonine-protein kinase Nek1	gencc,clinvar
PALLD	HGNC:17068	ENSG00000129116	Q8WX93	Palladin	clinvar
IFT54	HGNC:17861	ENSG00000204104	Q8TDR0	TRAF3-interacting protein 1	clinvar
EVC2	HGNC:19747	ENSG00000173040	Q86UK5	Limbin	clinvar
IFT74	HGNC:21424	ENSG00000096872	Q96LB3	Intraflagellar transport protein 74 homolog	clinvar
DYNC2LI1	HGNC:24595	ENSG00000138036	Q8TCX1	Cytoplasmic dynein 2 light intermediate chain 1	clinvar
TTC21B	HGNC:25660	ENSG00000123607	Q7Z4L5	Tetratricopeptide repeat protein 21B	clinvar
FUZ	HGNC:26219	ENSG00000010361	Q9BT04	Protein fuzzy homolog	clinvar
WDR35	HGNC:29250	ENSG00000118965	Q9P2L0	WD repeat-containing protein 35	clinvar
IFT80	HGNC:29262	ENSG00000068885	Q9P2H3	Intraflagellar transport protein 80 homolog	clinvar
DYNC2H1	HGNC:2962	ENSG00000187240	Q8NCM8	Cytoplasmic dynein 2 heavy chain 1	clinvar
IFT172	HGNC:30391	ENSG00000138002	Q9UG01	Intraflagellar transport protein 172 homolog	clinvar
EVC	HGNC:3497	ENSG00000072840	P57679	EvC complex member EVC	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NEK1	Serine/threonine-protein kinase Nek1	Phosphorylates serines and threonines, but also appears to possess tyrosine kinase activity.
PALLD	Palladin	Cytoskeletal protein required for organization of normal actin cytoskeleton.
IFT54	TRAF3-interacting protein 1	Plays an inhibitory role on IL13 signaling by binding to IL13RA1.
EVC2	Limbin	Component of the EvC complex that positively regulates ciliary Hedgehog (Hh) signaling.
IFT74	Intraflagellar transport protein 74 homolog	Component of the intraflagellar transport (IFT) complex B: together with IFT81, forms a tubulin-binding module that specifically mediates transport of tubulin within the cilium.
DYNC2LI1	Cytoplasmic dynein 2 light intermediate chain 1	Acts as one of several non-catalytic accessory components of the cytoplasmic dynein 2 complex (dynein-2 complex), a motor protein complex that drives the movement of cargos along microtubules within cilia and flagella in concert with the i…
TTC21B	Tetratricopeptide repeat protein 21B	Component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs).
FUZ	Protein fuzzy homolog	Probable planar cell polarity effector involved in cilium biogenesis.
WDR35	WD repeat-containing protein 35	As a component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport and entry into cilia of G protein-coupled receptors (GPCRs), it is involved in ciliogenesis and ciliary protein trafficking.
IFT80	Intraflagellar transport protein 80 homolog	Component of the intraflagellar transport (IFT) complex B, which is essential for the development and maintenance of motile and sensory cilia.
DYNC2H1	Cytoplasmic dynein 2 heavy chain 1	May function as a motor for intraflagellar retrograde transport.
IFT172	Intraflagellar transport protein 172 homolog	Required for the maintenance and formation of cilia.
EVC	EvC complex member EVC	Component of the EvC complex that positively regulates ciliary Hedgehog (Hh) signaling.

Protein-family classification

Druggable: 2 · Difficult: 3 · Unknown: 8 · Druggable fraction: 0.15

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	2	2.7×	0.563
Antibody/Immunoglobulin	1	2.2×	0.563
Kinase	1	2.1×	0.563
Other/Unknown	8	1.1×	0.563
Transcription factor	1	0.6×	0.813

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NEK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
PALLD	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
IFT54	Other/Unknown	no		TRAF3IP1, TRAF3IP1_N, TRAF3IP1_C
EVC2	Other/Unknown	no		Limbin, Limbin/EVC
IFT74	Other/Unknown	no		IFT74
DYNC2LI1	Other/Unknown	no		Dynein_light_int_chain, P-loop_NTPase, DYNC2LI1
TTC21B	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, TTC21A/TTC21B
FUZ	Other/Unknown	no		Fuzzy, FUZ/MON1/HPS1_longin_3, FUZ/MON1/HPS1_longin_2
WDR35	Transcription factor	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WDR35
IFT80	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf
DYNC2H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
IFT172	Scaffold/PPI	no		WD40_rpt, TPR-like_helical_dom_sf, WD40/YVTN_repeat-like_dom_sf
EVC	Other/Unknown	no		Limbin/EVC

Expression context

Cohort genes with no expression data: 0.

12 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)	13
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bronchial epithelial cell	6
right uterine tube	6
oocyte	2
secondary oocyte	2
sural nerve	2
calcaneal tendon	2
mucosa of paranasal sinus	2
left testis	2
trigeminal ganglion	1
blood vessel layer	1
heart right ventricle	1
saphenous vein	1
pancreatic ductal cell	1
primordial germ cell in gonad	1
caput epididymis	1
cerebellar hemisphere	1
right testis	1
bronchus	1
colonic epithelium	1
endothelial cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NEK1	288	ubiquitous	marker	secondary oocyte, trigeminal ganglion, oocyte
PALLD	302	ubiquitous	marker	saphenous vein, heart right ventricle, blood vessel layer
IFT54	265	ubiquitous	marker	oocyte, bronchial epithelial cell, sural nerve
EVC2	182	ubiquitous	marker	pancreatic ductal cell, calcaneal tendon, primordial germ cell in gonad
IFT74	272	ubiquitous	marker	bronchial epithelial cell, caput epididymis, right uterine tube
DYNC2LI1	293	ubiquitous	marker	right uterine tube, bronchial epithelial cell, mucosa of paranasal sinus
TTC21B	179	ubiquitous	marker	right uterine tube, calcaneal tendon, cerebellar hemisphere
FUZ	243	ubiquitous	marker	right uterine tube, right testis, left testis
WDR35	257	ubiquitous	marker	bronchial epithelial cell, mucosa of paranasal sinus, bronchus
IFT80	256	ubiquitous	marker	colonic epithelium, oviduct epithelium, endothelial cell
DYNC2H1	230	ubiquitous	marker	secondary oocyte, bronchial epithelial cell, right uterine tube
IFT172	236	ubiquitous	marker	right uterine tube, bronchial epithelial cell, left testis
EVC	163	ubiquitous	yes	sural nerve, stromal cell of endometrium, metanephros cortex

Protein interactions among cohort

Intra-cohort edges: 30.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IFT80	2,582
PALLD	2,362
IFT74	1,937
IFT172	1,922
DYNC2H1	1,885
TTC21B	1,588
NEK1	1,512
IFT54	1,363
WDR35	1,032
EVC2	913

Intra-cohort edges

A	B	Sources
DYNC2H1	DYNC2LI1	biogrid_interaction, intact, string_interaction
DYNC2H1	EVC	string_interaction
DYNC2H1	IFT172	string_interaction
DYNC2H1	IFT80	string_interaction
DYNC2H1	NEK1	string_interaction
DYNC2H1	TTC21B	string_interaction
DYNC2H1	WDR35	string_interaction
DYNC2LI1	EVC2	string_interaction
DYNC2LI1	IFT172	string_interaction
DYNC2LI1	IFT80	string_interaction
DYNC2LI1	WDR35	string_interaction
EVC	EVC2	string_interaction
EVC	IFT80	string_interaction
EVC	WDR35	string_interaction
EVC2	IFT80	string_interaction
EVC2	WDR35	string_interaction
FUZ	IFT54	string_interaction
FUZ	WDR35	string_interaction
IFT172	IFT54	biogrid_interaction, string_interaction
IFT172	IFT74	biogrid_interaction, string_interaction
IFT172	IFT80	biogrid_interaction, intact, string_interaction
IFT172	TTC21B	string_interaction
IFT172	WDR35	string_interaction
IFT54	IFT74	biogrid_interaction, string_interaction
IFT54	IFT80	string_interaction
IFT74	IFT80	biogrid_interaction, string_interaction
IFT74	TTC21B	string_interaction
IFT80	NEK1	string_interaction
IFT80	WDR35	string_interaction
TTC21B	WDR35	biogrid_interaction, intact, string_interaction

Structural data

PDB: 9 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
WDR35	Q9P2L0	4
DYNC2H1	Q8NCM8	4
DYNC2LI1	Q8TCX1	3
TTC21B	Q7Z4L5	3
FUZ	Q9BT04	3
NEK1	Q96PY6	2
PALLD	Q8WX93	2
IFT54	Q8TDR0	2
IFT172	Q9UG01	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
IFT80	Q9P2H3	92.50
IFT74	Q96LB3	81.21
EVC	P57679	74.49
EVC2	Q86UK5	73.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 13 evidence-associated genes (12 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 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Intraflagellar transport	8	133.6×	1e-15	IFT54, IFT74, DYNC2LI1, TTC21B, WDR35, IFT80, DYNC2H1, IFT172
Hedgehog ‘off’ state	5	74.3×	2e-08	TTC21B, FUZ, WDR35, DYNC2H1, IFT172
Activation of SMO	2	105.7×	6e-04	EVC2, EVC
Hedgehog ‘on’ state	2	26.4×	0.007	EVC2, EVC
Regulation of pyruvate metabolism	1	47.6×	0.050	NEK1
Pyruvate metabolism	1	34.0×	0.058	NEK1
Signaling by Hedgehog	1	15.3×	0.108	EVC2
Cilium Assembly	1	9.1×	0.157	IFT54
Aerobic respiration and respiratory electron transport	1	7.4×	0.170	NEK1
Organelle biogenesis and maintenance	1	5.5×	0.201	IFT54
Metabolism	1	1.0×	0.711	NEK1
Signal Transduction	1	0.8×	0.711	EVC2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 13 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cilium assembly	9	51.0×	1e-12	NEK1, IFT54, IFT74, TTC21B, FUZ, WDR35, IFT80, DYNC2H1 (+1 more)
intraciliary retrograde transport	4	345.7×	2e-08	DYNC2LI1, TTC21B, WDR35, DYNC2H1
non-motile cilium assembly	5	111.8×	2e-08	IFT74, FUZ, IFT80, DYNC2H1, IFT172
intraciliary anterograde transport	4	272.9×	2e-08	IFT54, IFT74, IFT80, IFT172
intraciliary transport	4	172.8×	1e-07	IFT54, FUZ, WDR35, IFT172
smoothened signaling pathway	5	69.7×	1e-07	EVC2, TTC21B, IFT80, IFT172, EVC
negative regulation of keratinocyte proliferation	3	162.0×	1e-05	IFT74, IFT80, IFT172
keratinocyte proliferation	3	134.1×	2e-05	IFT74, IFT80, IFT172
positive regulation of smoothened signaling pathway	3	97.2×	5e-05	DYNC2H1, IFT172, EVC
protein localization to cilium	3	92.6×	5e-05	TTC21B, WDR35, DYNC2H1
intraciliary transport involved in cilium assembly	2	370.4×	1e-04	IFT74, DYNC2LI1
determination of left/right symmetry	3	58.9×	2e-04	IFT74, DYNC2LI1, DYNC2H1
keratinocyte development	2	235.7×	3e-04	PALLD, IFT74
spinal cord motor neuron differentiation	2	144.0×	7e-04	DYNC2H1, IFT172
regulation of smoothened signaling pathway	2	96.0×	0.001	TTC21B, FUZ
regulation of cilium assembly	2	92.6×	0.002	DYNC2LI1, FUZ
negative regulation of smoothened signaling pathway	2	70.1×	0.002	IFT54, IFT172
dorsal/ventral pattern formation	2	64.8×	0.003	DYNC2H1, IFT172
limb development	2	63.2×	0.003	IFT80, IFT172
hindgut development	1	1296.3×	0.004	IFT172
negative regulation of neural crest formation	1	1296.3×	0.004	FUZ
regulation of intraciliary retrograde transport	1	648.1×	0.008	TTC21B
obsolete negative regulation of fibroblast growth factor receptor signaling pathway involved in neural plate anterior/posterior pattern formation	1	648.1×	0.008	FUZ
neural tube closure	2	28.8×	0.010	FUZ, IFT172
protein processing	2	26.2×	0.012	DYNC2H1, IFT172
morphogenesis of a polarized epithelium	1	324.1×	0.012	IFT54
growth plate cartilage chondrocyte differentiation	1	324.1×	0.012	IFT80
protein localization to non-motile cilium	1	324.1×	0.012	TTC21B
response to inositol	1	324.1×	0.012	IFT80
tooth eruption	1	259.3×	0.013	IFT80

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 12

Druggability breadth: 1 of 13 evidence-associated genes (8%) 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
NEK1	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NEK1	12	4
PALLD	0	0
IFT54	0	0
EVC2	0	0
IFT74	0	0
DYNC2LI1	0	0
TTC21B	0	0
FUZ	0	0
WDR35	0	0
IFT80	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	NEK1
DABRAFENIB	4	NEK1
LESTAURTINIB	3	NEK1
TG100-115	2	NEK1
R-406	2	NEK1
PELITINIB	2	NEK1
GSK-461364	1	NEK1
KW-2449	1	NEK1
AMG-900	1	NEK1
TAK-593	1	NEK1
CYC-116	1	NEK1
AST-487	1	NEK1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NEK1	288	Binding:288

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
NEK1	288

Pharmacogenomics

Cohort genes with a PharmGKB record: 13; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

12 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)
FEDRATINIB	4	NEK1
DABRAFENIB	4	NEK1
LESTAURTINIB	3	NEK1
TG100-115	2	NEK1
R-406	2	NEK1
PELITINIB	2	NEK1
GSK-461364	1	NEK1
KW-2449	1	NEK1
AMG-900	1	NEK1
TAK-593	1	NEK1
CYC-116	1	NEK1
AST-487	1	NEK1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NEK1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	PALLD
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	11	IFT54, EVC2, IFT74, DYNC2LI1, TTC21B, FUZ, WDR35, IFT80, DYNC2H1, IFT172 (+1 more)

Undrugged target profiles

12 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
DYNC2H1	0	NEK1
PALLD	0	—
IFT54	0	—
EVC2	0	—
IFT74	0	—
DYNC2LI1	0	—
TTC21B	0	—
FUZ	0	—
WDR35	0	—
IFT80	0	—
IFT172	0	—
EVC	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.