MKS1

Summary

MKS1 (MKS transition zone complex subunit 1, HGNC:7121) is a protein-coding gene on chromosome 17q22, encoding Tectonic-like complex member MKS1 (Q9NXB0). Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes.

The protein encoded by this gene localizes to the basal body and is required for formation of the primary cilium in ciliated epithelial cells. Mutations in this gene result in Meckel syndrome type 1 and in Bardet-Biedl syndrome type 13. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 54903 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ciliopathy (Definitive, ClinGen) — +7 more curated relationships
• GWAS associations: 8
• Clinical variants (ClinVar): 1,113 total — 61 pathogenic, 78 likely-pathogenic
• Phenotypes (HPO): 235
• MANE Select transcript: NM_017777

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7121
Approved symbol	MKS1
Name	MKS transition zone complex subunit 1
Location	17q22
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20345, POC12, BBS13
Ensembl gene	ENSG00000011143
Ensembl biotype	protein_coding
OMIM	609883
Entrez	54903

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 13 protein_coding, 12 retained_intron, 10 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000313863, ENST00000393119, ENST00000393120, ENST00000537529, ENST00000577824, ENST00000578789, ENST00000579358, ENST00000580127, ENST00000581180, ENST00000581761, ENST00000583577, ENST00000585134, ENST00000675753, ENST00000676787, ENST00000676975, ENST00000677076, ENST00000677111, ENST00000677160, ENST00000677416, ENST00000677475, ENST00000677486, ENST00000677546, ENST00000677709, ENST00000677791, ENST00000678011, ENST00000678211, ENST00000678432, ENST00000678463, ENST00000678481, ENST00000678568, ENST00000678641, ENST00000678763, ENST00000678928, ENST00000679081, ENST00000872459, ENST00000872460, ENST00000966002

RefSeq mRNA: 5 — MANE Select: NM_017777 NM_001321268, NM_001321269, NM_001330397, NM_001411113, NM_017777

CCDS: CCDS11603, CCDS82170, CCDS92364, CCDS92365

Canonical transcript exons

ENST00000393119 — 18 exons

Exon	Start	End
ENSE00001390723	58205441	58206170
ENSE00003459400	58206283	58206380
ENSE00003489895	58216088	58216243
ENSE00003496788	58207894	58208001
ENSE00003522954	58214741	58214838
ENSE00003599918	58210659	58210724
ENSE00003611671	58216666	58216736
ENSE00003614860	58207085	58207218
ENSE00003616896	58213765	58213869
ENSE00003619804	58218620	58218729
ENSE00003631561	58206465	58206547
ENSE00003639447	58212982	58213090
ENSE00003673370	58208105	58208174
ENSE00003681629	58212378	58212434
ENSE00003687863	58210980	58211022
ENSE00003691475	58214259	58214387
ENSE00003694300	58208513	58208583
ENSE00003896364	58219151	58219255

Expression profiles

Bgee: expression breadth ubiquitous, 182 present calls, max score 93.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.4771 / max 78.0470, expressed in 1763 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
167177	13.4771	1763

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	93.57	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	87.06	gold quality
left ovary	UBERON:0002119	85.55	gold quality
right ovary	UBERON:0002118	85.05	gold quality
ventricular zone	UBERON:0003053	84.82	gold quality
body of uterus	UBERON:0009853	84.14	gold quality
right adrenal gland	UBERON:0001233	84.08	gold quality
ganglionic eminence	UBERON:0004023	83.78	gold quality
metanephros cortex	UBERON:0010533	83.78	gold quality
sural nerve	UBERON:0015488	83.76	gold quality
right adrenal gland cortex	UBERON:0035827	83.72	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.43	gold quality
adenohypophysis	UBERON:0002196	83.20	gold quality
tibial nerve	UBERON:0001323	83.16	gold quality
body of pancreas	UBERON:0001150	83.00	gold quality
right testis	UBERON:0004534	82.86	gold quality
pituitary gland	UBERON:0000007	82.83	gold quality
skin of leg	UBERON:0001511	82.73	gold quality
right hemisphere of cerebellum	UBERON:0014890	82.69	gold quality
endocervix	UBERON:0000458	82.66	gold quality
right lobe of thyroid gland	UBERON:0001119	82.66	gold quality
apex of heart	UBERON:0002098	82.64	gold quality
left adrenal gland	UBERON:0001234	82.61	gold quality
left adrenal gland cortex	UBERON:0035825	82.31	gold quality
left testis	UBERON:0004533	82.28	gold quality
cerebellar hemisphere	UBERON:0002245	82.27	gold quality
ectocervix	UBERON:0012249	82.22	gold quality
cerebellar cortex	UBERON:0002129	82.16	gold quality
skin of abdomen	UBERON:0001416	82.12	gold quality
minor salivary gland	UBERON:0001830	82.05	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.44
E-GEOD-111727	no	847.87
E-MTAB-9801	no	2.88

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

26 targeting MKS1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-379-3P	99.69	69.60	1524
HSA-MIR-411-3P	99.69	69.63	1524
HSA-MIR-6848-3P	99.64	66.49	885
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-6843-3P	99.26	66.42	915
HSA-MIR-5100	99.11	67.52	1098
HSA-MIR-1288-5P	98.85	67.01	734
HSA-MIR-3922-5P	98.77	66.53	1059
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-6868-3P	98.63	69.64	2259
HSA-MIR-4704-3P	98.28	69.33	1300
HSA-MIR-4450	98.26	68.35	725
HSA-MIR-6810-3P	97.96	64.57	1023
HSA-MIR-193B-5P	97.91	65.88	837
HSA-MIR-10526-3P	97.86	64.97	1342
HSA-MIR-647	97.73	67.79	927
HSA-MIR-3936	97.64	64.47	732
HSA-MIR-4308	97.56	67.13	1385
HSA-MIR-550B-3P	95.43	67.73	599
HSA-MIR-4323	93.93	63.89	656

Literature-anchored findings (GeneRIF, showing 13)

• identification of a gene, MKS1,(Meckel syndrome) mutated in MKS families linked to 17q. (PMID:16415886)
• The Meckel-Gruber Syndrome proteins MKS1 and meckelin interact and are required for primary cilium formation. (PMID:17185389)
• Study concluded that MKS1 and MKS3 account for the majority of Meckel-Gruber syndrome; polydactyly is usually found in MKS1 but rare in MKS3; cases with no, or milder, CNS phenotypes were only found in MKS3. (PMID:17377820)
• genotyping of MKS1 & MKS3 genes in a large, multiethnic cohort of 120 independent cases of Meckel syndrome; first results indicate that the MKS1 & MKS3 genes are each responsible for about 7% of MKS cases with various mutations in different populations (PMID:17397051)
• Our results indicate that MKS1 mutations are not restricted to the Caucasian gene pool and suggest splicing defects are a crucial mutational mechanism in MKS1, and further genetic heterogeneity for MKS. (PMID:17437276)
• Mutations in MKS1 is associated with Bardet-Biedl syndrome (PMID:18327255)
• MKS-1 and MKS-1-related proteins 1 and 2 (MKSR-1, MKSR-2), localize to transition zones/basal bodies of sensory cilia; subcellular localization is largely co-dependent, pointing to a functional relationship between the proteins (PMID:19208769)
• Kidney tissue and cells from MKS1 and MKS3 patients showed defects in centrosome and cilia number, including multi-ciliated respiratory-like epithelia, and longer cilia. (PMID:19515853)
• describe four patients with mild Joubert phenotypes who carry pathogenic mutations in either MKS1 or B9D1, two genes previously implicated only in Meckel syndrome (PMID:24886560)
• MKS1 functions in the transition zone at the base of the cilium to regulate ciliary INPP5E content. (PMID:26490104)
• Dnah11(avc)(4) did not disrupt SHF Hh signaling and caused Atrioventricular septal defects (AVSDs) only concurrently with heterotaxy, a left/right axis abnormality. In contrast, Mks1(avc)(6) disrupted SHF Hh signaling and caused AVSDs without heterotaxy.We speculate that cilia gene mutations contribute to both syndromic and non-syndromic AVSDs in humans (PMID:27340223)
• we have described a pathogenic variant in the MKS1 resulting in a mild Joubert syndrome phenotype, which broadens the spectrum of mutations in the MKS1. (PMID:27570071)
• Formation of the B9-domain protein complex MKS1-B9D2-B9D1 is essential as a diffusion barrier for ciliary membrane proteins. (PMID:32726168)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mks1	ENSDARG00000059657
mus_musculus	Mks1	ENSMUSG00000034121
rattus_norvegicus	Mks1	ENSRNOG00000008635
drosophila_melanogaster	Mks1	FBGN0030395
caenorhabditis_elegans		WBGENE00020100

Paralogs (2): B9D1 (ENSG00000108641), B9D2 (ENSG00000123810)

Protein

Protein identifiers

Tectonic-like complex member MKS1 — Q9NXB0 (reviewed: Q9NXB0)

Alternative names: Meckel syndrome type 1 protein

All UniProt accessions (18): Q9NXB0, A0A0S2Z5Z2, A0A6Q8PG98, A0A6Q8PGJ4, A0A7I2V2M0, A0A7I2V4A2, A0A7I2V4C1, A0A7I2V4E1, A0A7I2V561, A0A7I2V6A2, A0A7I2YQA3, H0Y2S2, J3KRR3, J3KSB7, J3KSC6, J3KSF4, J3QQP4, J9PBQ5

UniProt curated annotations — full annotation on UniProt →

Function. Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes. Involved in centrosome migration to the apical cell surface during early ciliogenesis. Required for ciliary structure and function, including a role in regulating length and appropriate number through modulating centrosome duplication. Required for cell branching morphology.

Subunit / interactions. Part of the tectonic-like complex (also named B9 complex). Interacts with TMEM107. Interacts with TCTN3, AHI1, TCTN1, TCTN2, CC2D2A. Interacts with FLNA. Interacts with TMEM67. Interacts with B9D1 and B9D2.

Subcellular location. Cytoplasm. Cytoskeleton. Cilium basal body. Microtubule organizing center. Centrosome.

Disease relevance. Meckel syndrome 1 (MKS1) [MIM:249000] A disorder characterized by a combination of renal cysts and variably associated features including developmental anomalies of the central nervous system (typically encephalocele), hepatic ductal dysplasia and cysts, and polydactyly. The disease is caused by variants affecting the gene represented in this entry. Bardet-Biedl syndrome 13 (BBS13) [MIM:615990] A syndrome characterized by usually severe pigmentary retinopathy, early-onset obesity, polydactyly, hypogenitalism, renal malformation and intellectual disability. Secondary features include diabetes mellitus, hypertension and congenital heart disease. Bardet-Biedl syndrome inheritance is autosomal recessive, but three mutated alleles (two at one locus, and a third at a second locus) may be required for clinical manifestation of some forms of the disease. The disease is caused by variants affecting the gene represented in this entry. Joubert syndrome 28 (JBTS28) [MIM:617121] A form of Joubert syndrome, a disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy, renal disease, liver fibrosis, and polydactyly. JBTS28 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NXB0-1	1	yes
Q9NXB0-2	2
Q9NXB0-3	3

RefSeq proteins (5): NP_001308197, NP_001308198, NP_001317326, NP_001398042, NP_060247* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR010796	C2_B9-type_dom	Family

Pfam: PF07162

UniProt features (18 total): sequence variant 14, splice variant 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NXB0-F1	74.05	0.13

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-5610787	Hedgehog ‘off’ state
R-HSA-5620912	Anchoring of the basal body to the plasma membrane
R-HSA-162582	Signal Transduction
R-HSA-1852241	Organelle biogenesis and maintenance
R-HSA-5358351	Signaling by Hedgehog
R-HSA-5617833	Cilium Assembly

MSigDB gene sets: 587 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, MODULE_451, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_EMBRYONIC_DIGIT_MORPHOGENESIS, GOBP_EMBRYONIC_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_PROTEIN_LOCALIZATION_TO_CILIUM, GOBP_NON_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_REGULATION_OF_NON_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_NEUROGENESIS, GOBP_NEURAL_TUBE_DEVELOPMENT, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_MORPHOGENESIS_OF_EMBRYONIC_EPITHELIUM

GO Biological Process (21): neural tube closure (GO:0001843), smoothened signaling pathway involved in regulation of secondary heart field cardioblast proliferation (GO:0003271), determination of left/right symmetry (GO:0007368), regulation of smoothened signaling pathway (GO:0008589), epithelial structure maintenance (GO:0010669), dorsal/ventral neural tube patterning (GO:0021904), embryonic digit morphogenesis (GO:0042733), motile cilium assembly (GO:0044458), embryonic skeletal system development (GO:0048706), branching morphogenesis of an epithelial tube (GO:0048754), inner ear receptor cell stereocilium organization (GO:0060122), cilium assembly (GO:0060271), head development (GO:0060322), cardiac septum morphogenesis (GO:0060411), regulation of canonical Wnt signaling pathway (GO:0060828), common bile duct development (GO:0061009), non-motile cilium assembly (GO:1905515), embryonic brain development (GO:1990403), regulation of Wnt signaling pathway, planar cell polarity pathway (GO:2000095), regulation of secondary heart field cardioblast proliferation (GO:0003266), cell projection organization (GO:0030030)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (13): nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), centrosome (GO:0005813), centriole (GO:0005814), cytosol (GO:0005829), membrane (GO:0016020), MKS complex (GO:0036038), ciliary basal body (GO:0036064), cytoskeleton (GO:0005856), cilium (GO:0005929), ciliary transition zone (GO:0035869), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Signaling by Hedgehog	1
Assembly of the 9+0 primary cilium	1
Signal Transduction	1
Organelle biogenesis and maintenance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
intracellular membraneless organelle	3
microtubule organizing center	3
smoothened signaling pathway	2
cilium assembly	2
nuclear lumen	2
cilium	2
primary neural tube formation	1
tube closure	1
regulation of secondary heart field cardioblast proliferation	1
cell surface receptor signaling pathway involved in heart development	1
determination of bilateral symmetry	1
left/right pattern formation	1
regulation of signal transduction	1
tissue homeostasis	1
dorsal/ventral pattern formation	1
neural tube patterning	1
embryonic limb morphogenesis	1
embryonic morphogenesis	1
skeletal system development	1
chordate embryonic development	1
tube morphogenesis	1
epithelial tube morphogenesis	1
morphogenesis of a branching epithelium	1
neuron projection development	1
inner ear receptor cell development	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
anatomical structure development	1
cardiac chamber morphogenesis	1
cardiac septum development	1
anatomical structure morphogenesis	1
regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1

Protein interactions and networks

STRING

882 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MKS1	TCTN1	Q2MV58	987
MKS1	TMEM67	Q5HYA8	987
MKS1	CC2D2A	Q9P2K1	982
MKS1	CEP290	O15078	978
MKS1	NPHP1	O15259	960
MKS1	TMEM216	Q9P0N5	939
MKS1	B9D1	Q9UPM9	930
MKS1	TCTN2	Q96GX1	930
MKS1	NPHP4	O75161	904
MKS1	BBS10	Q8TAM1	904
MKS1	RPGRIP1L	Q68CZ1	892
MKS1	TMEM231	Q9H6L2	890
MKS1	TCTN3	Q6NUS6	890
MKS1	WDPCP	O95876	879
MKS1	BBS1	Q8NFJ9	871

IntAct

58 interactions, top by confidence:

A	B	Type	Score
B9D2	MKS1	psi-mi:“MI:0915”(physical association)	0.730
MKS1	B9D2	psi-mi:“MI:0915”(physical association)	0.730
ARPC5	ARPC3	psi-mi:“MI:0914”(association)	0.730
ENPP6	SCAMP1	psi-mi:“MI:0914”(association)	0.640
RCCD1	SPAG9	psi-mi:“MI:0914”(association)	0.640
TCTN2	TCTN3	psi-mi:“MI:0914”(association)	0.640
CAPN2	MYO9A	psi-mi:“MI:0914”(association)	0.530
TRIM35	MTA2	psi-mi:“MI:0914”(association)	0.530
PPIAL4G	ACTB	psi-mi:“MI:0914”(association)	0.530
B9D2	ANKRD40	psi-mi:“MI:0914”(association)	0.530
TMEM107	MKS1	psi-mi:“MI:0915”(physical association)	0.520
CC2D2A	OFD1	psi-mi:“MI:2364”(proximity)	0.420
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
KRT2	IFT56	psi-mi:“MI:0914”(association)	0.350
CDC16	IFT56	psi-mi:“MI:0914”(association)	0.350
PPP4R1L	IFT56	psi-mi:“MI:0914”(association)	0.350
CFAP184	TARS3	psi-mi:“MI:0914”(association)	0.350
LAGE3	HYKK	psi-mi:“MI:0914”(association)	0.350
DNAJA2	DENND11	psi-mi:“MI:0914”(association)	0.350
C6orf141	KRBA1	psi-mi:“MI:0914”(association)	0.350
GATD1	MYO9A	psi-mi:“MI:0914”(association)	0.350
THBS3	APBB1	psi-mi:“MI:0914”(association)	0.350
DOCK5	DPYSL4	psi-mi:“MI:0914”(association)	0.350
C1orf115	PRMT5	psi-mi:“MI:0914”(association)	0.350
ADAMTS4	RAD51B	psi-mi:“MI:0914”(association)	0.350
TGM2	MAP3K7	psi-mi:“MI:0914”(association)	0.350
	WDR62	psi-mi:“MI:0914”(association)	0.350

BioGRID (147): MKS1 (Affinity Capture-RNA), MKS1 (Affinity Capture-MS), MKS1 (Affinity Capture-MS), MKS1 (Affinity Capture-MS), MKS1 (Affinity Capture-MS), MKS1 (Affinity Capture-MS), MKS1 (Proximity Label-MS), AP3M1 (Proximity Label-MS), ARFGAP3 (Proximity Label-MS), B9D1 (Proximity Label-MS), B9D2 (Proximity Label-MS), R3HCC1L (Proximity Label-MS), CAD (Proximity Label-MS), CC2D1A (Proximity Label-MS), CCT2 (Proximity Label-MS)

ESM2 similar proteins: A1A4J7, A2A9C3, A2BID5, B1WC10, E7FAW3, E7FCN8, O02696, O15360, O75153, O75800, O95248, Q08D69, Q1JPG0, Q3U6Q4, Q499Q5, Q5BLE2, Q5SW28, Q5SW45, Q5T011, Q5U1Z0, Q5U249, Q5UE93, Q5ZIB8, Q6AXZ5, Q6GLY5, Q6GR21, Q6PGF3, Q6ZNJ1, Q6ZQA0, Q7L4E1, Q8BK03, Q8BM55, Q8BMG7, Q8C3S2, Q8CJF7, Q8ND04, Q8QZV7, Q8TC57, Q8VDR9, Q8VE18

Diamond homologs: M9MRD5, P0C5J3, Q3UK10, Q499Q5, Q56JY9, Q5SW45, Q6DGZ1, Q6GN70, Q9BPU9, Q9NXB0, P0C5J2, Q9UPM9

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 74 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Anchoring of the basal body to the plasma membrane	7	17.6×	4e-05
Cilium Assembly	6	14.5×	6e-04
Organelle biogenesis and maintenance	6	8.8×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
smoothened signaling pathway	7	19.2×	1e-05
cilium assembly	13	14.5×	2e-09

Disease & clinical

Clinical variants and AI predictions

ClinVar

1113 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	61
Likely pathogenic	78
Uncertain significance	390
Likely benign	443
Benign	24

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1072326	NM_017777.4(MKS1):c.918del (p.Val307fs)	Pathogenic
1074274	NM_017777.4(MKS1):c.811del (p.His271fs)	Pathogenic
1075466	NM_017777.4(MKS1):c.417+1G>T	Pathogenic
1076625	NC_000017.10:g.(?56296502)(56296882_?)del	Pathogenic
1323276	NM_017777.4(MKS1):c.1277C>G (p.Ser426Ter)	Pathogenic
1374939	NM_017777.4(MKS1):c.161T>A (p.Leu54Ter)	Pathogenic
1394	NM_017777.4(MKS1):c.1112_1114del (p.Phe371del)	Pathogenic
1417225	NM_017777.4(MKS1):c.469G>T (p.Glu157Ter)	Pathogenic
1420123	NM_017777.4(MKS1):c.639T>A (p.Tyr213Ter)	Pathogenic
1430465	NM_017777.4(MKS1):c.1204_1208dup (p.Leu404fs)	Pathogenic
1431885	NM_017777.4(MKS1):c.515+2T>C	Pathogenic
1442592	NM_017777.4(MKS1):c.856_857del (p.Asp286fs)	Pathogenic
1454042	NC_000017.10:g.(?56295971)(56296882_?)del	Pathogenic
1456571	NC_000017.10:g.(?56295969)(56296506_?)del	Pathogenic
1458565	NM_017777.4(MKS1):c.136G>T (p.Glu46Ter)	Pathogenic
1459148	NM_017777.4(MKS1):c.1301G>A (p.Trp434Ter)	Pathogenic
1460338	NM_017777.4(MKS1):c.925_926insTCTAA (p.Gly309delinsValTer)	Pathogenic
188334	NM_017777.4(MKS1):c.233T>G (p.Ile78Ser)	Pathogenic
188400	NM_017777.4(MKS1):c.1408-34_1408-6del	Pathogenic
191083	NM_017777.4(MKS1):c.1066C>T (p.Gln356Ter)	Pathogenic
1943755	NM_017777.4(MKS1):c.1024+1G>T	Pathogenic
2005996	NM_017777.4(MKS1):c.301_302dup (p.Ser101fs)	Pathogenic
2081577	NM_017777.4(MKS1):c.203del (p.Pro68fs)	Pathogenic
2107453	NM_017777.4(MKS1):c.114dup (p.Leu39fs)	Pathogenic
2113608	NM_017777.4(MKS1):c.1158del (p.Glu386fs)	Pathogenic
2127974	NM_017777.4(MKS1):c.1365del (p.Glu455fs)	Pathogenic
217673	NM_017777.4(MKS1):c.1528dup (p.Arg510fs)	Pathogenic
217674	NM_017777.4(MKS1):c.262-179_262-37del	Pathogenic
217676	NM_017777.4(MKS1):c.381del (p.Tyr128fs)	Pathogenic
217679	NM_017777.4(MKS1):c.950G>A (p.Gly317Glu)	Pathogenic

SpliceAI

2959 predictions. Top by Δscore:

Variant	Effect	Δscore
17:58206169:CT:C	acceptor_gain	1.0000
17:58206171:C:CC	acceptor_gain	1.0000
17:58206278:CATA:C	donor_loss	1.0000
17:58206279:ATAC:A	donor_loss	1.0000
17:58206281:ACC:A	donor_loss	1.0000
17:58206282:C:CG	donor_loss	1.0000
17:58206286:G:C	donor_gain	1.0000
17:58206377:GGCC:G	acceptor_gain	1.0000
17:58206378:GCCCT:G	acceptor_loss	1.0000
17:58206379:CC:C	acceptor_gain	1.0000
17:58206379:CCCTG:C	acceptor_loss	1.0000
17:58206380:CC:C	acceptor_gain	1.0000
17:58206380:CCTGC:C	acceptor_loss	1.0000
17:58206381:C:CC	acceptor_gain	1.0000
17:58206381:CTGCA:C	acceptor_loss	1.0000
17:58206382:T:A	acceptor_loss	1.0000
17:58206460:CTCA:C	donor_loss	1.0000
17:58206462:CACCT:C	donor_loss	1.0000
17:58206463:ACC:A	donor_loss	1.0000
17:58207081:TCAC:T	donor_loss	1.0000
17:58207094:T:TA	donor_gain	1.0000
17:58207219:C:CA	acceptor_loss	1.0000
17:58207309:G:C	donor_gain	1.0000
17:58207888:GGTTA:G	donor_loss	1.0000
17:58207889:GTTA:G	donor_loss	1.0000
17:58207890:TTACC:T	donor_loss	1.0000
17:58207891:TA:T	donor_loss	1.0000
17:58207892:A:C	donor_loss	1.0000
17:58207997:TGCAT:T	acceptor_gain	1.0000
17:58207998:GCAT:G	acceptor_gain	1.0000

AlphaMissense

3648 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:58216689:A:G	W80R	0.999
17:58216689:A:T	W80R	0.999
17:58216687:C:A	W80C	0.997
17:58216687:C:G	W80C	0.997
17:58216127:A:C	F126L	0.996
17:58216127:A:T	F126L	0.996
17:58216129:A:G	F126L	0.996
17:58206498:A:T	V486D	0.994
17:58214281:C:G	A208P	0.994
17:58216688:C:G	W80S	0.994
17:58213059:A:G	W261R	0.993
17:58213059:A:T	W261R	0.993
17:58213838:A:G	C226R	0.993
17:58216684:C:A	Q81H	0.993
17:58216684:C:G	Q81H	0.993
17:58213840:A:T	L225Q	0.992
17:58214280:G:T	A208E	0.992
17:58214286:A:T	I206N	0.992
17:58216669:G:C	S86R	0.992
17:58216669:G:T	S86R	0.992
17:58216671:T:G	S86R	0.992
17:58216678:C:A	K83N	0.991
17:58216678:C:G	K83N	0.991
17:58213053:A:C	Y263D	0.990
17:58210688:A:T	V332D	0.989
17:58216238:T:A	E89D	0.989
17:58216238:T:G	E89D	0.989
17:58216670:C:A	S86I	0.989
17:58213831:A:G	L228P	0.988
17:58216673:A:G	F85S	0.988

dbSNP variants (sampled 300 via entrez): RS1000404567 (17:58218202 A>G,T), RS1000943297 (17:58210519 G>A,C), RS1001270266 (17:58219813 T>C,G), RS1001515075 (17:58218321 G>A), RS1002134259 (17:58215145 A>G), RS1002258061 (17:58207720 G>A), RS1002549742 (17:58207248 G>A,C), RS1002602328 (17:58207044 A>G), RS1002761206 (17:58211518 G>T), RS1002942059 (17:58218371 C>G), RS1003188578 (17:58219693 G>A,C,T), RS1003412117 (17:58212691 A>T), RS1003429666 (17:58220113 A>G), RS1003579700 (17:58206490 G>A), RS1004485336 (17:58210153 G>T)

Disease associations

OMIM: gene MIM:609883 | disease phenotypes: MIM:249000, MIM:213300, MIM:615990, MIM:617121, MIM:108600, MIM:209900, MIM:603596, MIM:173900, MIM:613826

GenCC curated gene-disease

Disease	Classification	Inheritance
Bardet-Biedl syndrome 13	Definitive	Autosomal recessive
Meckel syndrome, type 1	Definitive	Autosomal recessive
Joubert syndrome 28	Strong	Autosomal recessive
ciliopathy	Strong	Autosomal recessive
Bardet-Biedl syndrome	Supportive	Autosomal recessive
Joubert syndrome with ocular defect	Supportive	Autosomal recessive
Joubert syndrome	Supportive	Autosomal recessive
Meckel syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
ciliopathy	Definitive	AR

Mondo (21): Meckel syndrome, type 1 (MONDO:0009571), Joubert syndrome (MONDO:0018772), Meckel syndrome (MONDO:0018921), Bardet-Biedl syndrome 13 (MONDO:0014441), Joubert syndrome 28 (MONDO:0014928), spastic ataxia (MONDO:0017845), pathologic nystagmus (MONDO:0004843), Bardet-Biedl syndrome (MONDO:0015229), polydactyly (MONDO:0021003), microcephaly (MONDO:0001149), retinal disorder (MONDO:0005283), chronic kidney disease (MONDO:0005300), optic atrophy (MONDO:0003608), inherited retinal dystrophy (MONDO:0019118), peripheral neuropathy (MONDO:0005244)

Orphanet (8): Isolated Joubert syndrome (Orphanet:475), Meckel syndrome (Orphanet:564), Bardet-Biedl syndrome (Orphanet:110), Spastic ataxia (Orphanet:316226), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Multicystic dysplastic kidney (Orphanet:1851), Leber congenital amaurosis (Orphanet:65), Joubert syndrome and related disorders (Orphanet:140874)

HPO phenotypes

235 total (30 of 235 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000007	Autosomal recessive inheritance
HP:0000011	Neurogenic bladder
HP:0000028	Cryptorchidism
HP:0000033	Ambiguous genitalia, male
HP:0000037	Male pseudohermaphroditism
HP:0000061	Ambiguous genitalia, female
HP:0000062	Ambiguous genitalia
HP:0000068	Urethral atresia
HP:0000069	Abnormality of the ureter
HP:0000073	Ureteral duplication
HP:0000076	Vesicoureteral reflux
HP:0000085	Horseshoe kidney
HP:0000100	Nephrotic syndrome
HP:0000104	Renal agenesis
HP:0000113	Polycystic kidney dysplasia
HP:0000119	Abnormality of the genitourinary system
HP:0000126	Hydronephrosis
HP:0000130	Abnormality of the uterus
HP:0000135	Hypogonadism
HP:0000147	Polycystic ovaries
HP:0000154	Wide mouth
HP:0000163	Abnormal oral cavity morphology
HP:0000175	Cleft palate
HP:0000180	Lobulated tongue
HP:0000202	Orofacial cleft
HP:0000204	Cleft upper lip
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000221	Furrowed tongue

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST003263_65	Post bronchodilator FEV1 in COPD	4.000000e-06
GCST003263_67	Post bronchodilator FEV1 in COPD	4.000000e-06
GCST003263_68	Post bronchodilator FEV1 in COPD	4.000000e-06
GCST003265_273	Post bronchodilator FEV1/FVC ratio in COPD	1.000000e-06
GCST003265_299	Post bronchodilator FEV1/FVC ratio in COPD	1.000000e-06
GCST003265_300	Post bronchodilator FEV1/FVC ratio in COPD	1.000000e-06
GCST90002381_537	Eosinophil count	7.000000e-14
GCST90002382_477	Eosinophil percentage of white cells	4.000000e-17

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004314	forced expiratory volume
EFO:0004713	FEV/FVC ratio
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes

MeSH disease descriptors (14)

Descriptor	Name	Tree numbers
D020788	Bardet-Biedl Syndrome	C10.228.140.617.200; C11.270.684.624; C16.131.077.245.125; C16.320.184.125
D007676	Kidney Failure, Chronic	C12.050.351.968.419.780.750.500; C12.200.777.419.780.750.500; C12.950.419.780.750.500; C23.550.291.500.906.500
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D021782	Multicystic Dysplastic Kidney	C12.050.351.875.558; C12.050.351.968.419.403.750; C12.200.706.629; C12.200.777.419.403.750; C12.800.629; C12.950.419.403.750; C16.131.939.629
D009759	Nystagmus, Pathologic	C10.292.562.675; C11.590.400
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D007690	Polycystic Kidney Diseases	C12.050.351.968.419.403.875; C12.200.777.419.403.875; C12.950.419.403.875; C16.131.077.717; C16.320.184.625
D017689	Polydactyly	C05.660.585.600; C16.131.621.585.600
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
C567140	Bardet-Biedl Syndrome 13 (supp.)
C565327	Leber Congenital Amaurosis 6 (supp.)
C536133	Meckel syndrome type 1 (supp.)
C564815	Spastic Ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
GSK-J4	decreases expression	1
methylmercuric chloride	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
beta-lapachone	decreases expression	1
sodium arsenite	decreases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
jinfukang	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Leflunomide	decreases expression	1
Acrolein	increases oxidation, increases abundance, affects cotreatment	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Benzo(a)pyrene	decreases methylation	1
Calcitriol	decreases expression, affects cotreatment	1
Estradiol	affects expression	1
Hydralazine	affects cotreatment, increases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Plant Extracts	affects cotreatment, increases expression	1
Testosterone	affects cotreatment, decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	affects cotreatment, increases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1
Acrylamide	decreases expression	1
Volatile Organic Compounds	affects cotreatment, increases oxidation	1

Clinical trials (associated diseases)

301 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01955135	PHASE4	COMPLETED	Anesthesia for Retinopathy of Prematurity
NCT00073710	PHASE4	COMPLETED	Study to Evaluate the Effects of Zemplar Injection and Calcijex on Intestinal Absorption of Calcium
NCT00125593	PHASE4	COMPLETED	Study of Heart and Renal Protection
NCT00132431	PHASE4	COMPLETED	START: Sensipar Treatment Algorithm to Reach K/DOQI Targets in Chronic Kidney Disease Subjects With Secondary Hyperparathyroidism
NCT00155246	PHASE4	COMPLETED	Efficacy of Pentoxifylline on Chronic Kidney Disease
NCT00175149	PHASE4	TERMINATED	Active Vitamin D Effect on Left Ventricular Hypertrophy
NCT00184769	PHASE4	COMPLETED	Growth Hormone Treatment in Infants Aged 1 to 2 Years With Chronic Renal Insufficiency (CRI) and Growth Retardation.
NCT00190580	PHASE4	COMPLETED	Kanagawa Valsartan Trial (KVT): Effects of Valsartan on Renal and Cardiovascular Disease
NCT00194961	PHASE4	TERMINATED	Effect of Growth Hormone on Leptin, Cytokines and Body Composition of Children With Growth Failure Due to Chronic Kidney Disease
NCT00239642	PHASE4	COMPLETED	Safety and Efficacy of Iron Sucrose in Children
NCT00324571	PHASE4	COMPLETED	Dialysis Clinical Outcomes Revisited (DCOR) Trial
NCT00364884	PHASE4	UNKNOWN	Keto-/Amino Acid Supplemented Low Protein Diet in Patients With Chronic Kidney Disease
NCT00368901	PHASE4	COMPLETED	STAAR-2 Clinical Study
NCT00369733	PHASE4	COMPLETED	STAAR-3 Clinical Study
NCT00369772	PHASE4	COMPLETED	STAAR-1 Clinical Study
NCT00379899	PHASE4	COMPLETED	ADVANCE: Study to Evaluate Cinacalcet Plus Low Dose Vitamin D on Vascular Calcification in Subjects With Chronic Kidney Disease Receiving Hemodialysis
NCT00384618	PHASE4	TERMINATED	Anti-Oxidant Therapy In Chronic Renal Insufficiency (ATIC) Study
NCT00478543	PHASE4	COMPLETED	Loop Diuretics in Chronic Kidney Disease
NCT00632125	PHASE4	COMPLETED	Post-authorization Safety Study in CKD Subjects Receiving HX575 i.v.
NCT00644046	PHASE4	COMPLETED	Chronic Kidney Disease Prevention of An-Lo District, Keelung
NCT00719316	PHASE4	UNKNOWN	Aliskiren and Muscle Sympathetic Nerve Activity
NCT00725517	PHASE4	COMPLETED	Efficacy and Safety of a 7.5% Icodextrin Peritoneal Dialysis Solution in Once-Daily Long Dwell Exchange
NCT00741585	PHASE4	COMPLETED	Prognostic Value of the Circadian Pattern of Ambulatory Blood Pressure for Multiple Risk Assessment
NCT00749736	PHASE4	COMPLETED	The Role of Vitamin D in Immune Function in Patients With Chronic Kidney Disease (CKD) Stages 3 and 4.
NCT00752102	PHASE4	COMPLETED	Vitamin D and Coronary Calcification Study
NCT00756145	PHASE4	COMPLETED	The Use of Low Molecular Weight Heparin in Hemodiafiltration
NCT00768638	PHASE4	COMPLETED	Study of Atorvastatin Dose Dependent Reduction of Proteinuria
NCT00786136	PHASE4	COMPLETED	Rosuvastatin Prevent Contrast Induced Acute Kidney Injury in Patients With Diabetes
NCT00803712	PHASE4	COMPLETED	20070360 Incident Dialysis
NCT00812123	PHASE4	COMPLETED	Calcineurin Free Immunosuppression in Renal Transplant Recipients
NCT00823303	PHASE4	COMPLETED	Paricalcitol Versus Calcitriol for Efficacy and Safety in Stage 3/4 Chronic Kidney Disease (CKD) With Secondary Hyperparathyroidism (SHPT)
NCT00830037	PHASE4	TERMINATED	A Clinical Trial of Oral Versus IV Iron in Patients With Chronic Kidney Disease
NCT00852969	PHASE4	COMPLETED	Niacin and Endothelial Function in Early CKD
NCT00858299	PHASE4	UNKNOWN	The Change of Urinary Angiotensinogen Excretion After Valsartan Treatment in Patients With Persistent Proteinuria
NCT00860431	PHASE4	COMPLETED	Kremezin Study Against Renal Disease Progression in Korea
NCT00882401	PHASE4	COMPLETED	Vitamin D, Chronic Kidney Disease (CKD) and the Microcirculation
NCT00889629	PHASE4	COMPLETED	Pilot Study Evaluating Doxercalciferol Replacement Therapy in Kidney Transplant Recipients
NCT00892892	PHASE4	WITHDRAWN	Sympathetic Nerve Activity in Renal Failure
NCT00893425	PHASE4	COMPLETED	Effect of Renin Angiotensin System Blockade on the Fas Antigen (CD95) and Asymmetric Dimethylarginine (ADMA) Levels in Type-2 Diabetic Patients With Proteinuria
NCT00908310	PHASE4	COMPLETED	Post-marketing Safety Study in Patients With Moderate Renal Insufficiency Who Receive Omniscan for Contrast-enhanced Magnetic Resonance Imaging (MRI)