MMS19

Summary

MMS19 (MMS19 cytosolic iron-sulfur assembly component, HGNC:13824) is a protein-coding gene on chromosome 10q24.1, encoding MMS19 nucleotide excision repair protein homolog (Q96T76). Key component of the cytosolic iron-sulfur protein assembly (CIA) complex, a multiprotein complex that mediates the incorporation of iron-sulfur cluster into apoproteins specifically involved in DNA metabolism and genomic integrity. It is a selective cancer dependency (DepMap: 87.8% of cell lines).

Enables nuclear estrogen receptor binding activity and transcription coactivator activity. Involved in protein maturation. Located in cytosol; nucleoplasm; and spindle. Part of MMXD complex and cytosolic [4Fe-4S] assembly targeting complex.

Source: NCBI Gene 64210 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodegenerative disease (Limited, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 190 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 87.8% of screened cell lines
• MANE Select transcript: NM_022362

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13824
Approved symbol	MMS19
Name	MMS19 cytosolic iron-sulfur assembly component
Location	10q24.1
Locus type	gene with protein product
Status	Approved
Aliases	MET18, hMMS19, CIAO4
Ensembl gene	ENSG00000155229
Ensembl biotype	protein_coding
OMIM	614777
Entrez	64210

Gene structure

Transcript identifiers

Ensembl transcripts: 47 — 36 protein_coding, 5 nonsense_mediated_decay, 5 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000327238, ENST00000355839, ENST00000370782, ENST00000415383, ENST00000422685, ENST00000434392, ENST00000434538, ENST00000437002, ENST00000438925, ENST00000439048, ENST00000441194, ENST00000444411, ENST00000448660, ENST00000477575, ENST00000478452, ENST00000480108, ENST00000483626, ENST00000485400, ENST00000495415, ENST00000896588, ENST00000896589, ENST00000896590, ENST00000896591, ENST00000896592, ENST00000896593, ENST00000896594, ENST00000896595, ENST00000896596, ENST00000896597, ENST00000896598, ENST00000896599, ENST00000896600, ENST00000896601, ENST00000896602, ENST00000896603, ENST00000896604, ENST00000896605, ENST00000896606, ENST00000896607, ENST00000933288, ENST00000933289, ENST00000933290, ENST00000933291, ENST00000933292, ENST00000971312, ENST00000971313, ENST00000971314

RefSeq mRNA: 9 — MANE Select: NM_022362 NM_001289403, NM_001289404, NM_001289405, NM_001330128, NM_001351356, NM_001351357, NM_001351358, NM_001351359, NM_022362

CCDS: CCDS73177, CCDS7464, CCDS81493

Canonical transcript exons

ENST00000438925 — 31 exons

Exon	Start	End
ENSE00001623251	97498273	97498422
ENSE00003487682	97460695	97460751
ENSE00003492117	97460907	97461007
ENSE00003504859	97476683	97476744
ENSE00003508757	97465805	97465954
ENSE00003517715	97468252	97468406
ENSE00003537742	97484103	97484151
ENSE00003545683	97458324	97458719
ENSE00003546459	97459362	97459526
ENSE00003549104	97480942	97481042
ENSE00003549717	97461496	97461622
ENSE00003554044	97470775	97470861
ENSE00003557949	97462017	97462119
ENSE00003559889	97469646	97469723
ENSE00003570787	97467505	97467583
ENSE00003577054	97478304	97478389
ENSE00003580455	97459223	97459282
ENSE00003583203	97466776	97466901
ENSE00003587583	97459659	97459741
ENSE00003615681	97477347	97477416
ENSE00003620516	97463858	97464013
ENSE00003632530	97461828	97461896
ENSE00003635415	97466059	97466159
ENSE00003644122	97458800	97458900
ENSE00003653375	97460046	97460232
ENSE00003663485	97466504	97466585
ENSE00003677396	97462583	97462682
ENSE00003679543	97477855	97477929
ENSE00003684088	97476835	97476963
ENSE00003688332	97468966	97469104
ENSE00003690714	97470129	97470203

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 96.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.5505 / max 149.6492, expressed in 1818 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
110936	35.5505	1818

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	96.88	gold quality
cerebellar hemisphere	UBERON:0002245	96.85	gold quality
cerebellar cortex	UBERON:0002129	96.79	gold quality
adenohypophysis	UBERON:0002196	96.45	gold quality
skin of leg	UBERON:0001511	96.32	gold quality
right testis	UBERON:0004534	96.25	gold quality
skin of abdomen	UBERON:0001416	96.03	gold quality
left testis	UBERON:0004533	96.01	gold quality
cerebellum	UBERON:0002037	95.94	gold quality
pituitary gland	UBERON:0000007	95.76	gold quality
tibial nerve	UBERON:0001323	95.27	gold quality
apex of heart	UBERON:0002098	95.27	gold quality
right ovary	UBERON:0002118	95.23	gold quality
ventricular zone	UBERON:0003053	95.23	gold quality
metanephros cortex	UBERON:0010533	95.23	gold quality
right frontal lobe	UBERON:0002810	95.22	gold quality
body of uterus	UBERON:0009853	95.08	gold quality
lower esophagus mucosa	UBERON:0035834	95.03	gold quality
right lung	UBERON:0002167	94.98	gold quality
ganglionic eminence	UBERON:0004023	94.98	gold quality
left ovary	UBERON:0002119	94.93	gold quality
ectocervix	UBERON:0012249	94.89	gold quality
testis	UBERON:0000473	94.87	gold quality
endocervix	UBERON:0000458	94.62	gold quality
right lobe of thyroid gland	UBERON:0001119	94.61	gold quality
sural nerve	UBERON:0015488	94.46	gold quality
zone of skin	UBERON:0000014	94.41	gold quality
right uterine tube	UBERON:0001302	94.41	gold quality
granulocyte	CL:0000094	94.40	gold quality
left lobe of thyroid gland	UBERON:0001120	94.37	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.39

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYCN

miRNA regulators (miRDB)

42 targeting MMS19, 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-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-4696	99.48	67.48	1040
HSA-MIR-4762-3P	99.43	69.72	2363
HSA-MIR-6719-3P	99.29	67.78	1387
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-922	99.02	67.23	1838

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 87.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 18)

• Cloning of the human MMS19 genes and functional complementation in Saccharomyces cerevisiae (PMID:11328871)
• MMS19 HEAT repeat domain is essential for MMS19 function in NER and transcription, while domains A and B, within MMS19 N-terminus, modulate the balance between DNA repair and transcription. (PMID:16797255)
• Single nucleotide polymorphisms in MMS19L is associated with pancreatic cancer. (PMID:19318433)
• Results indicate that the MMS19-XPD protein complex is required for proper chromosome segregation, an abnormality of which could contribute to the pathogenesis in some cases of xeroderma pigmentosum. (PMID:20797633)
• study demonstrates MMS19 forms a complex with the cytoplasmic Fe-S assembly (CIA) proteins CIAO1, IOP1 and MIP18; cytoplasmic MMS19 also binds to multiple nuclear Fe-S proteins involved in DNA metabolism; propose that MMS19 functions as a platform to facilitate Fe-S cluster transfer to proteins critical for DNA replication and repair (PMID:22678361)
• identified MMS19 as a member of the cytosolic iron-sulfur protein assembly (CIA) machinery; MMS19 functions as part of the CIA targeting complex that interacts with and facilitates iron-sulfur cluster insertion into apoproteins involved in methionine biosynthesis, DNA replication, DNA repair, and telomere maintenance (PMID:22678362)
• The mammalian proteins MMS19, MIP18, and ANT2 are involved in cytoplasmic iron-sulfur cluster protein assembly. (PMID:23150669)
• MMS19 interacts with target proteins. MIP18 has a role to bridge MMS19 and CIAO1. CIAO1 also binds IOP1. (PMID:23585563)
• Polymorphisms in ERCC1, codon-118 and MMS19 genes are not associated with clinical response to platinum or survival. (PMID:23632208)
• Single nucleotide polymorphisms in the MMS19L gene is associated with bone malignant tumors. (PMID:23679317)
• MMS19L polymorphisms are associated with response to chemotherapy in osteosarcoma. (PMID:23886164)
• Suggest that MMS19 may be a potential new predictor of metastasis and chemoradiotherapy response in esophageal squamous cell carcinoma. (PMID:25892874)
• POLE1 is phosphorylated at serine-1940 after DNA damage and interacts with the iron-sulfur complex chaperones CIAO1 and MMS19. (PMID:27235625)
• We therefore propose the expression level of MMS19 as a candidate predictive marker of ACT benefit in resected NSCLC patients. (PMID:27802208)
• findings suggest that MMS19 plays an essential role in maintaining mitochondrial genome stability (PMID:29035693)
• Structural insights into Fe-S protein biogenesis by the CIA targeting complex. (PMID:32632277)
• The c-MYC transcription factor conduces to resistance to cisplatin by regulating MMS19 in bladder cancer cells. (PMID:37201439)
• CIAO1 and MMS19 deficiency: A lethal neurodegenerative phenotype caused by cytosolic Fe-S cluster protein assembly disorders. (PMID:38411040)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mms19	ENSDARG00000079067
mus_musculus	Mms19	ENSMUSG00000025159
rattus_norvegicus	Mms19	ENSRNOG00000046769
drosophila_melanogaster	Mms19	FBGN0037301
caenorhabditis_elegans		WBGENE00016060

Protein

Protein identifiers

MMS19 nucleotide excision repair protein homolog — Q96T76 (reviewed: Q96T76)

Alternative names: MET18 homolog, MMS19-like protein

All UniProt accessions (8): Q96T76, B0QZ77, F8WCH8, H0Y746, H0Y7V3, H7C0A9, H7C1W5, Q5T454

UniProt curated annotations — full annotation on UniProt →

Function. Key component of the cytosolic iron-sulfur protein assembly (CIA) complex, a multiprotein complex that mediates the incorporation of iron-sulfur cluster into apoproteins specifically involved in DNA metabolism and genomic integrity. In the CIA complex, MMS19 acts as an adapter between early-acting CIA components and a subset of cellular target iron-sulfur proteins such as ERCC2/XPD, FANCJ and RTEL1, thereby playing a key role in nucleotide excision repair (NER), homologous recombination-mediated double-strand break DNA repair, DNA replication and RNA polymerase II (POL II) transcription. As part of the mitotic spindle-associated MMXD complex, plays a role in chromosome segregation, probably by facilitating iron-sulfur (Fe-S) cluster assembly into ERCC2/XPD. Together with CIAO2, facilitates the transfer of Fe-S clusters to the motor protein KIF4A, which ensures proper localization of KIF4A to mitotic machinery components to promote the progression of mitosis. Indirectly acts as a transcriptional coactivator of estrogen receptor (ER), via its role in iron-sulfur insertion into some component of the TFIIH-machinery.

Subunit / interactions. Component of the CIA complex. In the CIA complex, interacts directly with CIAO2B and CIAO3. Component of the MMXD complex, composed of CIAO1, ERCC2, CIAO2B, MMS19 and SLC25A5. Interacts with CIAO2B; the interaction is direct. Interacts with ERCC2/XPD; the interaction is direct. Interacts with ERCC3/XPB and NCOA3/RAC3. Interacts with RTEL1; the interaction mediates the association of RTEL1 with the CIA complex. Interacts with BRIP1. Interacts with KIF4A; the interaction facilitates the transfer of Fe-S clusters to KIF4A to ensure proper localization of KIF4A to the mitotic machinery components. Interacts with CCDC117; the interaction is indirect.

Subcellular location. Nucleus. Cytoplasm. Cytoskeleton. Spindle. Microtubule organizing center. Centrosome.

Tissue specificity. Ubiquitously expressed with higher expression in testis.

Post-translational modifications. Ubiquitinated; undergoes ‘Lys-48’-linked polyubiquitination by MAGEF1-NSMCE1 ubiquitin ligase complex leading to proteasomal degradation.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the MET18/MMS19 family.

Isoforms (6)

UniProt ID	Names	Canonical?
Q96T76-1	1	yes
Q96T76-7	2
Q96T76-6	3
Q96T76-5	4
Q96T76-8	5
Q96T76-9	6

RefSeq proteins (9): NP_001276332, NP_001276333, NP_001276334, NP_001317057, NP_001338285, NP_001338286, NP_001338287, NP_001338288, NP_071757* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR024687	MMS19_C	Domain
IPR029240	MMS19_N	Domain
IPR039920	MMS19	Family

Pfam: PF12460, PF14500

UniProt features (40 total): sequence variant 11, sequence conflict 9, splice variant 7, repeat 4, mutagenesis site 4, modified residue 3, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96T76-F1	91.00	0.75

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): 2, 496, 1027

Mutagenesis-validated functional residues (4):

Position	Phenotype
993	impairs magef1-nsmce1-mediated polyubiquitination when associated with r-1002, 1007-r-r-1008 and r-1013.
1002	impairs magef1-nsmce1-mediated polyubiquitination when associated with r-993, 1007-r-r-1008 and r-1013.
1007–1008	impairs magef1-nsmce1-mediated polyubiquitination when associated with r-993, r-1002 and r-1013.
1013	impairs magef1-nsmce1-mediated polyubiquitination when associated with r-993, r-1002 and 1007-r-r-1008.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2564830	Cytosolic iron-sulfur cluster assembly
R-HSA-1430728	Metabolism

MSigDB gene sets: 150 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GSE45365_NK_CELL_VS_CD8_TCELL_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, MORF_HDAC2, KAUFFMANN_DNA_REPAIR_GENES, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_PROTEIN_MATURATION, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOCC_CENTROSOME, MORF_RFC4, MORF_PRKDC, GOBP_DNA_DAMAGE_RESPONSE, GOCC_RNA_POLYMERASE_COMPLEX, MORF_AATF, GOCC_SPINDLE

GO Biological Process (6): DNA repair (GO:0006281), chromosome segregation (GO:0007059), protein maturation (GO:0051604), DNA damage response (GO:0006974), iron-sulfur cluster assembly (GO:0016226), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (6): transcription coactivator activity (GO:0003713), enzyme binding (GO:0019899), signaling receptor complex adaptor activity (GO:0030159), nuclear estrogen receptor binding (GO:0030331), protein-macromolecule adaptor activity (GO:0030674), protein binding (GO:0005515)

GO Cellular Component (11): nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription factor TFIIH holo complex (GO:0005675), cytoplasm (GO:0005737), centrosome (GO:0005813), spindle (GO:0005819), cytosol (GO:0005829), membrane (GO:0016020), MMXD complex (GO:0071817), cytosolic [4Fe-4S] assembly targeting complex (GO:0097361), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
protein binding	2
intracellular membraneless organelle	2
DNA metabolic process	1
DNA damage response	1
cell cycle process	1
gene expression	1
protein metabolic process	1
cellular response to stress	1
metallo-sulfur cluster assembly	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
signaling receptor binding	1
signaling adaptor activity	1
nuclear receptor binding	1
molecular adaptor activity	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
transcription factor TFIIH core complex	1
RNA polymerase II, holoenzyme	1
nuclear cyclin-dependent protein kinase holoenzyme complex	1
carboxy-terminal domain protein kinase complex	1
RNA polymerase II transcription regulator complex	1
intracellular anatomical structure	1
centriole	1
microtubule organizing center	1
microtubule cytoskeleton	1
cytoplasm	1
spindle	1
protein-containing complex	1
intracellular protein-containing complex	1
iron-sulfur cluster assembly complex	1

Protein interactions and networks

STRING

1722 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MMS19	CIAO1	O76071	997
MMS19	CIAO2B	Q9Y3D0	997
MMS19	CIAO3	Q9H6Q4	975
MMS19	SLC25A5	P05141	948
MMS19	SLC25A6	P12236	918
MMS19	CIAO2A	Q9H5X1	904
MMS19	NUBP1	P53384	877
MMS19	ERCC2	P18074	816
MMS19	RTEL1	Q9NZ71	807
MMS19	CIAPIN1	Q6FI81	795
MMS19	BRIP1	Q9BX63	745
MMS19	XPA	P23025	721
MMS19	DNA2	P51530	715
MMS19	LYRM4	Q9HD34	666
MMS19	NFS1	Q9Y697	666

IntAct

166 interactions, top by confidence:

A	B	Type	Score
HRAS	RAF1	psi-mi:“MI:0914”(association)	0.980
CIAO2B	CIAO1	psi-mi:“MI:0914”(association)	0.950
CIAO2B	CIAO1	psi-mi:“MI:0915”(physical association)	0.950
BRIP1	MLH1	psi-mi:“MI:0914”(association)	0.940
SPC24	NDC80	psi-mi:“MI:0914”(association)	0.920
MMS19	CIAO1	psi-mi:“MI:0914”(association)	0.910
MMS19	CIAO1	psi-mi:“MI:0915”(physical association)	0.910
CIAO1	MMS19	psi-mi:“MI:0915”(physical association)	0.910
MMS19	CIAO2B	psi-mi:“MI:0915”(physical association)	0.830
CIAO2B	MMS19	psi-mi:“MI:0915”(physical association)	0.830
MMS19	CIAO2B	psi-mi:“MI:0407”(direct interaction)	0.830
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710

BioGRID (471): MMS19 (Two-hybrid), MMS19 (Affinity Capture-Western), RTEL1 (Affinity Capture-Western), FAM96B (Affinity Capture-MS), CIAO1 (Affinity Capture-MS), NARFL (Affinity Capture-MS), POLD1 (Affinity Capture-MS), PRIM2 (Affinity Capture-MS), DNA2 (Affinity Capture-MS), ERCC2 (Affinity Capture-MS), BRIP1 (Affinity Capture-MS), RTEL1 (Affinity Capture-MS), CDKAL1 (Affinity Capture-MS), TYW1 (Affinity Capture-MS), NDUFS2 (Affinity Capture-MS)

ESM2 similar proteins: A0JMW2, A2VE70, A5WW24, A7E2Y6, B9EJR8, E0CZ22, E1BP36, E7FBU4, O35638, O43156, O70576, O75155, Q08AM6, Q0P5A6, Q0V9L1, Q16401, Q5IFJ8, Q5JTH9, Q5R6L5, Q5ZIW5, Q5ZKD5, Q66L58, Q68F38, Q6DCF2, Q6P5B0, Q6ZQ73, Q7TMY7, Q80W92, Q80WQ2, Q84ZC0, Q86Y56, Q8C0Y0, Q8K2V6, Q8NDA8, Q8WVM7, Q91V83, Q96T76, Q99M76, Q9BPX3, Q9D071

Diamond homologs: E1BP36, E7FBU4, Q0V9L1, Q6DCF2, Q96T76, Q9D071

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MMS19	“form complex”	“CIAO2B cytosolic iron-sulfur protein assembly complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 161 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
Cytosolic iron-sulfur cluster assembly	7	51.2×	2e-08

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to vascular endothelial growth factor stimulus	5	20.1×	1e-03
MAPK cascade	8	8.8×	1e-03
protein autophosphorylation	8	8.3×	1e-03
positive regulation of MAPK cascade	11	6.3×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	145
Likely benign	7
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

4608 predictions. Top by Δscore:

Variant	Effect	Δscore
10:97458799:CCA:C	donor_gain	1.0000
10:97458804:C:CA	donor_gain	1.0000
10:97458805:C:A	donor_gain	1.0000
10:97458824:T:TA	donor_gain	1.0000
10:97458898:CAG:C	acceptor_gain	1.0000
10:97458899:AG:A	acceptor_gain	1.0000
10:97458899:AGC:A	acceptor_loss	1.0000
10:97458900:GCT:G	acceptor_loss	1.0000
10:97458901:C:CA	acceptor_loss	1.0000
10:97458901:C:CC	acceptor_gain	1.0000
10:97458902:T:A	acceptor_loss	1.0000
10:97459217:ACTT:A	donor_loss	1.0000
10:97459218:CTT:C	donor_loss	1.0000
10:97459219:TTACC:T	donor_loss	1.0000
10:97459221:A:AC	donor_gain	1.0000
10:97459222:C:A	donor_loss	1.0000
10:97459222:C:CC	donor_gain	1.0000
10:97459222:CCA:C	donor_gain	1.0000
10:97459222:CCACA:C	donor_gain	1.0000
10:97459279:CAGC:C	acceptor_gain	1.0000
10:97459283:C:CC	acceptor_gain	1.0000
10:97460043:CACCT:C	donor_loss	1.0000
10:97460044:A:C	donor_loss	1.0000
10:97460045:C:CA	donor_loss	1.0000
10:97460090:T:C	donor_gain	1.0000
10:97460163:C:CT	acceptor_gain	1.0000
10:97461006:CC:C	acceptor_gain	1.0000
10:97461007:CC:C	acceptor_gain	1.0000
10:97461008:C:CC	acceptor_gain	1.0000
10:97461826:A:AC	donor_gain	1.0000

AlphaMissense

6670 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:97458801:A:G	W1022R	0.998
10:97458801:A:T	W1022R	0.998
10:97468357:A:C	S371R	0.998
10:97468357:A:T	S371R	0.998
10:97468359:T:G	S371R	0.998
10:97458831:G:T	R1012S	0.997
10:97458838:T:A	R1009S	0.997
10:97458838:T:G	R1009S	0.997
10:97476888:A:G	L190P	0.997
10:97458822:C:G	A1015P	0.996
10:97458839:C:G	R1009T	0.996
10:97470130:A:G	L282P	0.996
10:97469653:C:G	R306P	0.995
10:97470139:A:G	L279P	0.995
10:97470812:A:G	L245P	0.995
10:97470824:A:G	L241P	0.995
10:97477397:C:G	R148P	0.995
10:97458830:C:G	R1012P	0.994
10:97476689:A:C	F226L	0.994
10:97476689:A:T	F226L	0.994
10:97476691:A:G	F226L	0.994
10:97459714:A:G	L895P	0.993
10:97461522:G:T	A762E	0.993
10:97461529:A:G	C760R	0.993
10:97468349:A:G	L374P	0.993
10:97458821:G:T	A1015E	0.992
10:97476906:T:A	E184V	0.992
10:97468391:A:G	L360P	0.991
10:97470178:T:A	K266I	0.991
10:97477927:G:C	S117R	0.991

dbSNP variants (sampled 300 via entrez): RS1000082728 (10:97468926 T>C), RS1000088355 (10:97462027 T>C), RS1000199230 (10:97484033 T>A,C,G), RS1000244245 (10:97487350 G>A), RS1000244617 (10:97484417 C>G), RS1000315998 (10:97487520 C>T), RS1000397993 (10:97490472 G>A), RS1000476121 (10:97468710 G>T), RS1000592083 (10:97493846 T>A,C), RS1000646784 (10:97498950 C>A,T), RS1000829373 (10:97493517 T>C), RS1000842442 (10:97472239 A>T), RS1000875691 (10:97476309 C>T), RS1000962964 (10:97496542 G>A,T), RS1001040853 (10:97479794 T>C)

Disease associations

OMIM: gene MIM:614777 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodegenerative disease	Limited	Autosomal recessive

Mondo (1): neurodegenerative disease (MONDO:0005559)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST008178_10	Early spontaneous preterm birth	3.000000e-06
GCST008180_6	Spontaneous preterm birth with premature rupture of membranes	2.000000e-06
GCST012226_333	Waist circumference adjusted for body mass index	5.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006917	spontaneous preterm birth
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D019636	Neurodegenerative Diseases	C10.574

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066469 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.01	Kd	970.4	nM	CHEMBL3752910
6.01	ED50	970.4	nM	CHEMBL3752910
5.89	Kd	1301	nM	CHEMBL5653589
5.89	ED50	1301	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148759: Binding affinity to human MMS19 incubated for 45 mins by Kinobead based pull down assay	kd	0.9704	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148759: Binding affinity to human MMS19 incubated for 45 mins by Kinobead based pull down assay	kd	1.3014	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, decreases expression, affects cotreatment, increases abundance	3
bisphenol A	affects cotreatment, increases methylation, increases expression	2
Arsenic	affects expression, affects cotreatment, decreases expression, increases abundance	2
Tobacco Smoke Pollution	decreases expression	2
GSK-J4	increases expression	1
bisphenol F	increases expression	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
isobutyl alcohol	affects cotreatment, increases abundance, increases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
jinfukang	increases expression	1
bisphenol AF	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Ethanol	increases expression, affects cotreatment, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Fluorouracil	affects reaction, decreases expression	1
Gasoline	affects cotreatment, increases abundance, increases expression	1
Ivermectin	decreases expression	1
Manganese	decreases expression, increases abundance, affects cotreatment	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, increases abundance, increases expression	1
Selenium	affects cotreatment, increases expression	1
Thiram	decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	affects expression	1
Vitamin E	affects cotreatment, increases expression	1
Aflatoxin B1	decreases methylation	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651801	Binding	Binding affinity to human MMS19 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01662414	PHASE4	COMPLETED	Effect of Undenatured Cysteine-Rich Whey Protein Isolate (HMS 90®) in Patients With Parkinson’s Disease
NCT04871464	PHASE4	UNKNOWN	Role and Mechanism of Probiotics in Improving Motor Symptoms in Mild to Moderate Parkinson’s Disease
NCT05357612	PHASE4	RECRUITING	Characterization of the Serotonin 2A Receptor Selective PET Tracer [18F]MH.MZ in Patients With Neurodegenerative Diseases
NCT05508789	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Donanemab (LY3002813) in Participants With Early Symptomatic Alzheimer’s Disease (TRAILBLAZER-ALZ 5)
NCT05738486	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Different Donanemab (LY3002813) Dosing Regimens in Adults With Early Alzheimer’s Disease (TRAILBLAZER-ALZ 6)
NCT06111014	PHASE3	TERMINATED	Continuation Study for Latozinemab
NCT06672237	PHASE3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT00001365	PHASE2	COMPLETED	Dextromethorphan for the Treatment of Parkinson’s Disease and Similar Conditions of the Nervous System
NCT00406029	PHASE2	COMPLETED	Dyskinesia in Parkinson’s Disease (Study P04501)
NCT00537017	PHASE2	COMPLETED	Follow Up Safety Study of SCH 420814 in Subjects With Parkinson’s Disease (P05175)
NCT00907283	PHASE2	UNKNOWN	Ferrochelating Treatment in Patients Affected by Neurodegeneration With Brain Iron Accumulation (NBIA)
NCT01518374	PHASE2	COMPLETED	Clinical Evaluation of Florbetapir F 18 (18F-AV-45)
NCT02656498	PHASE2	COMPLETED	[18F]THK-5351 Positron Emission Computed Tomography Study of Normal, Mild Cognitive Impairment, Alzheimer’s Disease and Other Neurodegenerative Disease
NCT03127514	PHASE2	COMPLETED	AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT03538522	PHASE2	COMPLETED	A Double-Blind, Placebo-Controlled Safety and Efficacy Study of NA-831
NCT04838301	PHASE2	RECRUITING	Allopregnanolone Regenerative Therapeutic for Mild Alzheimer’s Disease
NCT04937452	PHASE2	COMPLETED	Dopaminergic Therapy for Frontotemporal Dementia Patients
NCT05318976	PHASE2	COMPLETED	A Study of XPro1595 in Patients With Early Alzheimer’s Disease With Biomarkers of Inflammation
NCT05321498	PHASE2	WITHDRAWN	Study to Assess the Efficacy of XPro1595 in Patients With Mild Cognitive Impairment With Biomarkers of Inflammation
NCT05479981	PHASE2	COMPLETED	Extension of AOC 1001-CS1 (MARINA) Study in Adult Myotonic Dystrophy Type 1 (DM1) Patients
NCT05522387	PHASE2	TERMINATED	An Open-Label Extension of XPro1595 in Patients With Alzheimer’s Disease
NCT00316797	PHASE1	COMPLETED	Biodistribution and Safety of a Radiopharmaceutical in Healthy Subjects
NCT01758510	PHASE1	COMPLETED	Safety Study of HLA-haplo Matched Allogenic Bone Marrow Derived Stem Cell Treatment in Amyotrophic Lateral Sclerosis
NCT02267434	PHASE1	COMPLETED	Study Assessing Tolerability and Safety of AFFITOPE® PD03A in Patients With Early Parkinson’s Disease
NCT02270489	PHASE1	COMPLETED	Study Assessing Safety and Therapeutic Activity of AFFITOPE® PD01A and PD03A in Patients With Early MSA
NCT03065192	PHASE1	COMPLETED	Safety and Efficacy Study of VY-AADC01 for Advanced Parkinson’s Disease
NCT04578028	PHASE1	COMPLETED	A First in Human Study to Assess the Safety, Tolerability and Pharmacokinetics of ONO-2808-01 in Healthy Participants
NCT05143463	PHASE1	COMPLETED	A FIH Study to Assess the Safety and Tolerability of NS Intravenous NS101 Infusion
NCT05490576	PHASE1	UNKNOWN	Tau And Connectomics In TES Study
NCT05792163	PHASE1	COMPLETED	A First Time in Human Study of SNP318 as a Treatment for Neurodegenerative Diseases Including Alzheimer’s Disease
NCT07232147	PHASE1	NOT_YET_RECRUITING	Clinical Research on Stem Cell Therapy for Parkinson’s Disease
NCT03143374	PHASE2/PHASE3	RECRUITING	PET Tau - Neurodegenerative Disease Imaging
NCT06122662	PHASE2/PHASE3	COMPLETED	AMX0035 and Progressive Supranuclear Palsy
NCT03295786	PHASE1/PHASE2	COMPLETED	Clinical Study to Test the Safety of CDNF by Brain Infusion in Patients With Parkinson’s Disease
NCT05853471	PHASE1/PHASE2	UNKNOWN	[18F]MC225-PET in Neurodegenerative Disease
NCT06447194	PHASE1/PHASE2	WITHDRAWN	Effect of RECK in Posterior Spinal Fusion
NCT06934720	PHASE1/PHASE2	NOT_YET_RECRUITING	VR-based Physical Activity and Reminiscence Therapy
NCT02452216	EARLY_PHASE1	COMPLETED	Using Ferumoxytol-Enhanced MRI to Measure Inflammation in Patients With Brain Tumors or Other Conditions of the CNS
NCT04575727	EARLY_PHASE1	COMPLETED	Exploratory Evaluation of [11C]MPC6827
NCT06181513	EARLY_PHASE1	RECRUITING	Probiotics in Mild Alzheimer’s Disease