CNNM4

Summary

CNNM4 (cyclin and CBS domain divalent metal cation transport mediator 4, HGNC:105) is a protein-coding gene on chromosome 2q11.2, encoding Metal transporter CNNM4 (Q6P4Q7). Probable metal transporter.

This gene encodes a member of the ancient conserved domain containing protein family. Members of this protein family contain a cyclin box motif and have structural similarity to the cyclins. The encoded protein may play a role in metal ion transport. Mutations in this gene are associated with Jalili syndrome which consists of cone-rod dystrophy and amelogenesis imperfecta.

Source: NCBI Gene 26504 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Jalili syndrome (Definitive, ClinGen)
• GWAS associations: 5
• Clinical variants (ClinVar): 582 total — 33 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 25
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_020184

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:105
Approved symbol	CNNM4
Name	cyclin and CBS domain divalent metal cation transport mediator 4
Location	2q11.2
Locus type	gene with protein product
Status	Approved
Aliases	SLC70A4, KIAA1592
Ensembl gene	ENSG00000158158
Ensembl biotype	protein_coding
OMIM	607805
Entrez	26504

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000377075, ENST00000482716, ENST00000493384, ENST00000496186, ENST00000930282, ENST00000966765

RefSeq mRNA: 1 — MANE Select: NM_020184 NM_020184

CCDS: CCDS2024

Canonical transcript exons

ENST00000377075 — 7 exons

Exon	Start	End
ENSE00001037348	96808561	96808742
ENSE00001037357	96809320	96811874
ENSE00001071928	96760902	96762401
ENSE00003478814	96797513	96797647
ENSE00003624061	96799057	96799226
ENSE00003628156	96799552	96799648
ENSE00003650175	96797012	96797155

Expression profiles

Bgee: expression breadth ubiquitous, 189 present calls, max score 92.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.9939 / max 788.0031, expressed in 1759 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
21480	10.8021	1727
21479	0.5484	299
21484	0.2589	58
21478	0.2570	78
21485	0.0687	23
21483	0.0588	24

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	92.61	gold quality
rectum	UBERON:0001052	92.09	gold quality
ileal mucosa	UBERON:0000331	89.49	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.29	gold quality
colonic mucosa	UBERON:0000317	89.20	gold quality
mucosa of sigmoid colon	UBERON:0004993	88.17	gold quality
transverse colon	UBERON:0001157	86.53	gold quality
right hemisphere of cerebellum	UBERON:0014890	86.43	gold quality
cerebellar hemisphere	UBERON:0002245	86.21	gold quality
muscle of leg	UBERON:0001383	86.10	gold quality
cerebellar cortex	UBERON:0002129	86.10	gold quality
gastrocnemius	UBERON:0001388	85.80	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	85.71	silver quality
apex of heart	UBERON:0002098	85.67	gold quality
cerebellum	UBERON:0002037	84.89	gold quality
muscle organ	UBERON:0001630	84.60	gold quality
triceps brachii	UBERON:0001509	84.17	silver quality
right uterine tube	UBERON:0001302	84.14	gold quality
heart left ventricle	UBERON:0002084	83.22	gold quality
cardiac ventricle	UBERON:0002082	82.82	gold quality
gluteal muscle	UBERON:0002000	82.12	silver quality
large intestine	UBERON:0000059	81.94	gold quality
colon	UBERON:0001155	81.94	gold quality
skeletal muscle tissue	UBERON:0001134	81.66	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.51	gold quality
islet of Langerhans	UBERON:0000006	81.38	gold quality
biceps brachii	UBERON:0001507	81.26	gold quality
cortical plate	UBERON:0005343	80.78	gold quality
intestine	UBERON:0000160	80.68	gold quality
colonic epithelium	UBERON:0000397	80.28	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.10

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

158 targeting CNNM4, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-548AJ-5P	99.78	71.12	3085

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 22)

• Identification of CNNM4 as the causative gene for Jalili syndrome, characterized by autosomal-recessive cone-rod dystrophy and amelogenesis imperfecta. (PMID:19200525)
• Since CNNM4 is implicated in metal ion transport, cone-rod dystrophy and amelogenesis imperfecta may originate from abnormal ion homeostasis. (PMID:19200527)
• This work describes the purification and preliminary crystallographic analysis of the CBS-pair regulatory domain of the human ancient domain protein 4 (ACDP4), also known as CNNM4. (PMID:21393841)
• Our case shows a unique combination of NF1 and Jalili syndrome; clinical examination, but also of molecular genetic analysis, which together provide a precise diagnosis. (PMID:21728811)
• The c.1312 dupC mutation of CNNM4 leads to a premature termination of amelogenesis resulting in thin, incompletely mineralized enamel, whereas in dentin, only mineralization is disturbed. (PMID:24194943)
• These results demonstrate the crucial importance of Mg(2+) extrusion by CNNM4 in organismal and topical regulation of magnesium. (PMID:24339795)
• Data indicate that a mutation in the cystathionine-beta-synthase (CBS) domains of ancient conserved domain protein 4/cyclin M4 CNNM4 completely abrogated their Mg2+ efflux functions. (PMID:24706765)
• these results indicate that CNNM4-dependent Mg(2+) efflux suppresses tumor progression by regulating energy metabolism. (PMID:25347473)
• CNNM4 is sorted to the basolateral membrane by the complementary function of AP-1A and AP-1B (PMID:25449265)
• These results suggest a new role of CNNM4 in sperm Ca(2+) homeostasis. (PMID:27006114)
• We describe three siblings with clinical features of Jalili syndrome with a homozygous missense mutation in exon 4 of CNNM4, c.1781A>G (p.N594S). (PMID:27070327)
• We identified a novel homozygous deleterious mutation in CNNM4 gene which causes Jalili syndrome. (PMID:27419834)
• used Sanger sequencing to analyze a large consanguineous family with three siblings affected with Jalili syndrome, suspected clinically after dental and ophthalmological examination. These patients are carrying a novel homozygous mutation in the splice site acceptor of intron 3 (c.1682-1G > C) in the CNNM4 gene (PMID:28246031)
• Mutational analysis showed in all three brothers a novel likely pathogenic homozygous missense substitution in exon 1 (c.1076T>C, p.(Leu359Pro)) of CNNM4. Both parents were carriers for the variant. (PMID:28586144)
• Results identified linkage at chromosome 2p14-2q14 and found a homozygous mutation in the CNNM4 gene (p.R605X) causing Jalili syndrome. The truncated CNNM4 protein starting at R605 significantly increased the rate of apoptosis, and significantly increased the interaction between CNNM4 and IQCB1. This mutation may cause Jalili syndrome by a nonsense-mediated decay mechanism, affecting the function of IQCB1 and apoptosis. (PMID:29322253)
• Jalili Syndrome is a rare cone-rod dystrophy (CORD) and amelogenesis imperfecta (AI), We have further characterized its ocular phenotype, including describing SD-OCT, FAF, and electrophysiological features; and report several novel disease-causing sequence variants. (PMID:29421294)
• Here, we report the 2 first families with Jalili Syndrome in Brazil. Molecular analysis of the first family identified a previously described homozygous mutation (p.Leu324Pro) in exon 1 of CNNM4 gene. In the second family, affected patients demonstrated a compound heterozygous mutation in CNNM4, the p.Leu324Pro and the novel nonsense mutation p.Tyr581*. (PMID:29421602)
• The novel identified variant in CNNM4 is the first report from the Pakistani population. Sequence analysis of CNNM4 revealed a novel missense variant (c.1220G>T, p.Arg407Leu) in exon-1 encoding cystathionine-beta-synthase (CBS) domain. (PMID:31347285)
• Expanding the genotypic spectrum of Jalili syndrome: Novel CNNM4 variants and uniparental isodisomy in a north American patient cohort. (PMID:32022389)
• CNNM proteins selectively bind to the TRPM7 channel to stimulate divalent cation entry into cells. (PMID:34928937)
• Novel CNNM4 variant and clinical features of Jalili syndrome. (PMID:36354001)
• Dimerization of the CNNM extracellular domain. (PMID:38149326)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	cnnm4b	ENSDARG00000074309
danio_rerio	cnnm4a	ENSDARG00000102380
danio_rerio	si:ch211-230g14.6	ENSDARG00000103737
		ENSDARG00000114841
mus_musculus	Cnnm4	ENSMUSG00000037408
rattus_norvegicus	Cnnm4	ENSRNOG00000015886
drosophila_melanogaster	uex	FBGN0262124
caenorhabditis_elegans		WBGENE00011260
caenorhabditis_elegans		WBGENE00016343
caenorhabditis_elegans		WBGENE00016879

Paralogs (3): CNNM1 (ENSG00000119946), CNNM2 (ENSG00000148842), CNNM3 (ENSG00000168763)

Protein

Protein identifiers

Metal transporter CNNM4 — Q6P4Q7 (reviewed: Q6P4Q7)

Alternative names: Ancient conserved domain-containing protein 4, Cyclin-M4

All UniProt accessions (1): Q6P4Q7

UniProt curated annotations — full annotation on UniProt →

Function. Probable metal transporter. The interaction with the metal ion chaperone COX11 suggests that it may play a role in sensory neuron functions. May play a role in biomineralization and retinal function.

Subunit / interactions. Interacts with COX11.

Subcellular location. Cell membrane.

Tissue specificity. Widely expressed. Highly expressed in heart.

Disease relevance. Jalili syndrome (JALIS) [MIM:217080] A syndrome characterized by the association of cone-rod dystrophy and amelogenesis imperfecta. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Shares weak sequence similarity with the cyclin family, explaining its name. However, it has no cyclin-like function in vivo.

Similarity. Belongs to the ACDP family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6P4Q7-1	1	yes
Q6P4Q7-2	2

RefSeq proteins (1): NP_064569* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000595	cNMP-bd_dom	Domain
IPR000644	CBS_dom	Domain
IPR002550	CNNM	Domain
IPR014710	RmlC-like_jellyroll	Homologous_superfamily
IPR018490	cNMP-bd_dom_sf	Homologous_superfamily
IPR044751	Ion_transp-like_CBS	Domain
IPR045095	ACDP	Family
IPR046342	CBS_dom_sf	Homologous_superfamily
IPR057492	Ig_CNNM1/2/4_N	Domain

Pfam: PF00571, PF01595, PF25511, PF25562

Enzyme classification (BRENDA):

• EC 7.2.2.14 — P-type Mg2+ transporter (BRENDA: 30 organisms, 43 substrates, 51 inhibitors, 23 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
MG2+	0.006–0.05	8
NI2+	0.002–0.4	5
ATP	1.5–2.8	2
CO2+	0.04–0.08	2
MG2+[SIDE 1]	0.01–0.015	2

UniProt features (27 total): sequence variant 6, topological domain 5, domain 3, modified residue 3, transmembrane region 3, glycosylation site 2, splice variant 2, chain 1, sequence conflict 1, intramembrane region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6G52	X-RAY DIFFRACTION	3.69
6RS2	X-RAY DIFFRACTION	3.69

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6P4Q7-F1	77.20	0.36

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3): 660, 664, 770

Glycosylation sites (2): 85, 122

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 201 (showing top): PEREZ_TP63_TARGETS, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, MODULE_493, GOBP_TOOTH_MINERALIZATION, GOBP_MAGNESIUM_ION_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_ENAMEL_MINERALIZATION, AML_Q6, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, GOBP_AMELOGENESIS, PEREZ_TP53_AND_TP63_TARGETS, RYTTCCTG_ETS2_B, GOBP_SENSORY_PERCEPTION, GOBP_MONOATOMIC_ION_HOMEOSTASIS

GO Biological Process (9): visual perception (GO:0007601), magnesium ion homeostasis (GO:0010960), magnesium ion transport (GO:0015693), intracellular monoatomic cation homeostasis (GO:0030003), enamel mineralization (GO:0070166), monoatomic ion transport (GO:0006811), biomineral tissue development (GO:0031214), sodium ion transmembrane transport (GO:0035725), magnesium ion transmembrane transport (GO:1903830)

GO Molecular Function (3): sodium ion transmembrane transporter activity (GO:0015081), magnesium ion transmembrane transporter activity (GO:0015095), protein binding (GO:0005515)

GO Cellular Component (4): plasma membrane (GO:0005886), basolateral plasma membrane (GO:0016323), protein-containing complex (GO:0032991), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
monoatomic cation homeostasis	2
monoatomic cation transmembrane transport	2
metal ion transmembrane transporter activity	2
sensory perception of light stimulus	1
inorganic ion homeostasis	1
metal ion transport	1
intracellular monoatomic ion homeostasis	1
tooth mineralization	1
amelogenesis	1
transport	1
tissue development	1
animal organ development	1
sodium ion transport	1
magnesium ion transport	1
sodium ion transmembrane transport	1
magnesium ion transmembrane transport	1
binding	1
membrane	1
cell periphery	1
basal plasma membrane	1
plasma membrane region	1
cellular_component	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1352 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CNNM4	H7C2H4	H7C2H4	850
CNNM4	COX11	Q9Y6N1	843
CNNM4	P0DN79	P0DN79	836
CNNM4	MMP20	O60882	717
CNNM4	SLC41A1	Q8IVJ1	694
CNNM4	TRPM6	Q9BX84	676
CNNM4	MMP25	Q9NPA2	675
CNNM4	TRPM7	Q96QT4	589
CNNM4	NIPAL3	Q6P499	584
CNNM4	CNGA3	Q16281	561
CNNM4	NIPAL2	Q9H841	557
CNNM4	NIPAL1	Q6NVV3	554
CNNM4	FAM20A	Q96MK3	547
CNNM4	PTP4A3	O75365	539
CNNM4	NIPAL4	Q0D2K0	521
CNNM4	NIPA2	Q8N8Q9	521

IntAct

79 interactions, top by confidence:

A	B	Type	Score
CD9	ADAM10	psi-mi:“MI:0914”(association)	0.750
PTP4A1	CNNM4	psi-mi:“MI:0914”(association)	0.740
PTP4A2	CNNM4	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PTP4A2	PTP4A3	psi-mi:“MI:0914”(association)	0.640
MRPS30	GTPBP10	psi-mi:“MI:0914”(association)	0.640
ARL15	SLC25A20	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
PTP4A1	ATE1	psi-mi:“MI:0914”(association)	0.530
STK16	UNC119B	psi-mi:“MI:0914”(association)	0.530
ARMC6	SLC27A2	psi-mi:“MI:0914”(association)	0.530
LGALS1	LAMA5	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
UNC93B1	GPR89A	psi-mi:“MI:0914”(association)	0.530
PTP4A1	PSMD3	psi-mi:“MI:0914”(association)	0.420
PTP4A2	USP11	psi-mi:“MI:2364”(proximity)	0.420
PTP4A1	PSMD3	psi-mi:“MI:2364”(proximity)	0.420
IQCB1	CEP290	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
P2RY6	ESYT2	psi-mi:“MI:0914”(association)	0.350
UNC93B1		psi-mi:“MI:0914”(association)	0.350
P2RY6		psi-mi:“MI:0914”(association)	0.350
CUL3	PXDNL	psi-mi:“MI:0914”(association)	0.350
LRRC39	GSN	psi-mi:“MI:0914”(association)	0.350
MBLAC2	STAT3	psi-mi:“MI:0914”(association)	0.350
PTP4A1	FDFT1	psi-mi:“MI:0914”(association)	0.350
PTP4A2	SPTBN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (102): CNNM4 (Affinity Capture-MS), CNNM4 (Affinity Capture-MS), CNNM4 (Affinity Capture-MS), CNNM4 (Affinity Capture-MS), CNNM4 (Affinity Capture-MS), CNNM4 (Affinity Capture-MS), CNNM4 (Affinity Capture-MS), CNNM4 (Affinity Capture-MS), CNNM4 (Affinity Capture-MS), CNNM4 (Affinity Capture-MS), CNNM4 (Affinity Capture-MS), CNNM4 (Affinity Capture-MS), CNNM4 (Affinity Capture-RNA), CNNM4 (Affinity Capture-RNA), CNNM4 (Affinity Capture-MS)

ESM2 similar proteins: A0A0B7P9G0, A0A131MCZ8, A2PYH4, A3QM97, B4JXX2, B4QZU1, E1BPX4, G5EBX9, O00835, O13768, O14072, O74431, P32639, P36583, P36775, P38329, P39986, P40527, P47047, P53273, P53914, P87115, P91119, P92006, Q07093, Q09769, Q12296, Q21029, Q3UYK3, Q55EJ3, Q67XQ0, Q6BMW3, Q6CNR9, Q6FPE6, Q6P4Q7, Q6ZT07, Q84K47, Q8RY60, Q9BMK9, Q9FKF2

Diamond homologs: A0A0B7P9G0, A0A131MCZ8, A0JPA0, A3QM97, A8EZU0, A8F2M1, A8GPR9, A8GTI4, A8GUH1, O05961, P0C588, Q0GA42, Q12296, Q1RGX2, Q32NY4, Q3TWN3, Q4UK99, Q4V3C7, Q54318, Q57368, Q5U2P1, Q67XQ0, Q68W10, Q69ZF7, Q6P4Q7, Q8NE01, Q8RY60, Q8VZI2, Q92GI2, Q9GYL2, Q9H8M5, Q9LTD8, Q9NRU3, Q9USJ3, Q9ZQR4, Q9ZVS8, Q9CM13, Q9LK65, O05241, O07589

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	33
Likely pathogenic	15
Uncertain significance	291
Likely benign	189
Benign	22

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1054444	NM_020184.4(CNNM4):c.2130+1G>A	Pathogenic
1069696	NM_020184.4(CNNM4):c.279del (p.Phe93fs)	Pathogenic
1070169	NM_020184.4(CNNM4):c.620_621del (p.Met207fs)	Pathogenic
1342702	NM_020184.4(CNNM4):c.1475G>A (p.Gly492Asp)	Pathogenic
1440136	NM_020184.4(CNNM4):c.2148C>A (p.Tyr716Ter)	Pathogenic
1443458	NM_020184.4(CNNM4):c.154dup (p.Ala52fs)	Pathogenic
1450679	NM_020184.4(CNNM4):c.750del (p.Asn250fs)	Pathogenic
1454983	NC_000002.11:g.(?97462002)(97464855_?)del	Pathogenic
2005741	NM_020184.4(CNNM4):c.1475del (p.Gly492fs)	Pathogenic
2013699	NM_020184.4(CNNM4):c.86del (p.Leu29fs)	Pathogenic
2025646	NM_020184.4(CNNM4):c.1234G>T (p.Glu412Ter)	Pathogenic
2036150	NM_020184.4(CNNM4):c.340del (p.Asp114fs)	Pathogenic
2084124	NM_020184.4(CNNM4):c.1813C>T (p.Arg605Ter)	Pathogenic
2114369	NM_020184.4(CNNM4):c.1759G>T (p.Glu587Ter)	Pathogenic
2133625	NM_020184.4(CNNM4):c.1964del (p.His655fs)	Pathogenic
2203115	NM_020184.4(CNNM4):c.1091del (p.Gly364fs)	Pathogenic
252931	NM_020184.4(CNNM4):c.1682-1G>C	Pathogenic
2580955	NM_020184.4(CNNM4):c.1034T>A (p.Leu345Ter)	Pathogenic
2768104	NM_020184.4(CNNM4):c.2035_2053dup (p.Gln685fs)	Pathogenic
2788411	NM_020184.4(CNNM4):c.471_484del (p.Asp157fs)	Pathogenic
2849	NM_020184.4(CNNM4):c.971T>C (p.Leu324Pro)	Pathogenic
2850	NM_020184.4(CNNM4):c.1690C>T (p.Gln564Ter)	Pathogenic
2851	NM_020184.4(CNNM4):c.599C>A (p.Ser200Tyr)	Pathogenic
2853	NM_020184.4(CNNM4):c.64_147del (p.Ala22_Met49del)	Pathogenic
3249983	NM_020184.4(CNNM4):c.9_55del (p.Val4fs)	Pathogenic
434794	NM_020184.4(CNNM4):c.1555C>T (p.Arg519Ter)	Pathogenic
518456	NM_020184.4(CNNM4):c.1743C>G (p.Tyr581Ter)	Pathogenic
635490	NM_020184.4(CNNM4):c.1312del (p.Leu438fs)	Pathogenic
801734	NM_020184.4(CNNM4):c.1547-1G>A	Pathogenic
812291	NM_020184.4(CNNM4):c.1494C>A (p.Asp498Glu)	Pathogenic

SpliceAI

1486 predictions. Top by Δscore:

Variant	Effect	Δscore
2:96762397:GAAGG:G	donor_gain	1.0000
2:96762399:AGGGT:A	donor_loss	1.0000
2:96762400:GG:G	donor_gain	1.0000
2:96762400:GGGTA:G	donor_loss	1.0000
2:96762401:GG:G	donor_gain	1.0000
2:96762402:G:GG	donor_gain	1.0000
2:96762403:T:G	donor_loss	1.0000
2:96797007:CACA:C	acceptor_loss	1.0000
2:96797009:CA:C	acceptor_loss	1.0000
2:96797010:A:AG	acceptor_gain	1.0000
2:96797010:AG:A	acceptor_gain	1.0000
2:96797010:AGG:A	acceptor_gain	1.0000
2:96797011:G:A	acceptor_gain	1.0000
2:96797011:G:GG	acceptor_gain	1.0000
2:96797011:GGG:G	acceptor_gain	1.0000
2:96797011:GGGA:G	acceptor_gain	1.0000
2:96797011:GGGAA:G	acceptor_gain	1.0000
2:96797151:GTACA:G	donor_gain	1.0000
2:96797152:TACA:T	donor_gain	1.0000
2:96797152:TACAG:T	donor_loss	1.0000
2:96797153:ACA:A	donor_gain	1.0000
2:96797154:CAG:C	donor_loss	1.0000
2:96797155:AGTG:A	donor_loss	1.0000
2:96797156:G:C	donor_loss	1.0000
2:96797156:G:GG	donor_gain	1.0000
2:96797157:T:A	donor_loss	1.0000
2:96797507:C:CA	acceptor_gain	1.0000
2:96797508:GGCA:G	acceptor_loss	1.0000
2:96797509:GCAG:G	acceptor_loss	1.0000
2:96797510:CAG:C	acceptor_loss	1.0000

AlphaMissense

5084 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:96761640:T:C	L214P	1.000
2:96762096:T:C	L366P	1.000
2:96762102:T:C	L368P	1.000
2:96762174:T:A	L392Q	1.000
2:96762174:T:C	L392P	1.000
2:96762179:T:C	F394L	1.000
2:96762181:C:A	F394L	1.000
2:96762181:C:G	F394L	1.000
2:96762216:C:T	T406I	1.000
2:96762218:C:A	R407S	1.000
2:96762218:C:G	R407G	1.000
2:96762219:G:C	R407P	1.000
2:96762224:C:T	P409S	1.000
2:96762225:C:A	P409Q	1.000
2:96762225:C:G	P409R	1.000
2:96762228:T:A	V410E	1.000
2:96762264:T:A	L422H	1.000
2:96762264:T:C	L422P	1.000
2:96762273:A:T	K425I	1.000
2:96762276:A:T	D426V	1.000
2:96762279:T:C	L427S	1.000
2:96762279:T:G	L427W	1.000
2:96762282:C:A	A428D	1.000
2:96762329:T:C	F444L	1.000
2:96762330:T:C	F444S	1.000
2:96762331:C:A	F444L	1.000
2:96762331:C:G	F444L	1.000
2:96762354:T:A	V452D	1.000
2:96762356:T:C	F453L	1.000
2:96762358:C:A	F453L	1.000

dbSNP variants (sampled 300 via entrez): RS1000044748 (2:96796462 A>C), RS1000156632 (2:96794952 C>A,T), RS1000230338 (2:96790583 A>C), RS1000231695 (2:96769631 C>T), RS1000298489 (2:96761148 G>C), RS1000304030 (2:96781903 A>C,G), RS1000410644 (2:96760907 G>C), RS1000487012 (2:96807235 T>C), RS1000539943 (2:96781943 A>G), RS1000549607 (2:96794496 A>G), RS1000583732 (2:96769230 A>G), RS1000593239 (2:96789075 G>T), RS1000751532 (2:96807468 CA>C,CAA), RS1000857765 (2:96802355 C>T), RS1000952129 (2:96802171 G>GAT)

Disease associations

OMIM: gene MIM:607805 | disease phenotypes: MIM:217080, MIM:268000

GenCC curated gene-disease

Disease	Classification	Inheritance
Jalili syndrome	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Jalili syndrome	Definitive	AR

Mondo (3): Jalili syndrome (MONDO:0009007), retinitis pigmentosa (MONDO:0019200), inherited retinal dystrophy (MONDO:0019118)

Orphanet (3): Jalili syndrome (Orphanet:1873), Retinitis pigmentosa (Orphanet:791), OBSOLETE: Inherited retinal disorder (Orphanet:71862)

HPO phenotypes

25 total (26 of 25 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000505	Visual impairment
HP:0000543	Optic disc pallor
HP:0000548	Cone/cone-rod dystrophy
HP:0000551	Color vision defect
HP:0000575	Scotoma
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000662	Nyctalopia
HP:0000670	Carious teeth
HP:0000682	Abnormal dental enamel morphology
HP:0000705	Amelogenesis imperfecta
HP:0003593	Infantile onset
HP:0006286	Yellow-brown discoloration of the teeth
HP:0007401	Macular atrophy
HP:0007703	Abnormal retinal pigmentation
HP:0007737	Spicular pigmentation of the retina
HP:0007803	Monochromacy
HP:0007814	Retinal pigment epithelial mottling
HP:0007843	Attenuation of retinal blood vessels
HP:0008499	High hypermetropia
HP:0011073	Abnormality of dental color
HP:0012043	Pendular nystagmus
HP:0033785	Enamel agenesis
HP:0000556	Retinal dystrophy

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001241_9	Bipolar disorder	2.000000e-06
GCST003962_1	Bipolar disorder	3.000000e-10
GCST006865_6	Bipolar disorder	3.000000e-06
GCST008103_13	Bipolar disorder	4.000000e-09
GCST009600_30	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	1.000000e-09

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
C000596385	Jalili syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

32 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	increases expression	3
Benzo(a)pyrene	increases expression, increases methylation	3
Valproic Acid	affects methylation, increases expression, increases methylation	3
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
(+)-JQ1 compound	increases expression	2
Arsenic Trioxide	affects binding, decreases reaction, decreases response to substance	2
Cyclosporine	increases expression	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
K 7174	increases expression	1
licochalcone B	increases expression	1
Aldehydes	decreases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Doxorubicin	decreases expression	1
Manganese	increases abundance, increases expression, affects cotreatment	1
Phenobarbital	affects expression	1
Quercetin	increases expression	1
Sulindac	increases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	increases expression	1
Aflatoxin B1	increases methylation	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)
NCT00063765	PHASE1	COMPLETED	Evaluation of Safety of Ciliary Neurotrophic Factor Implants in the Eye
NCT00065455	PHASE1	COMPLETED	Investigating the Effect of Vitamin A Supplementation on Retinitis Pigmentosa
NCT00458575	PHASE1	TERMINATED	A Study to Evaluate the Safety of CNTO 2476 in Patients With Advanced Retinitis Pigmentosa
NCT01068561	PHASE1	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa