MTPAP

Summary

MTPAP (mitochondrial poly(A) polymerase, HGNC:25532) is a protein-coding gene on chromosome 10p11.23, encoding Poly(A) RNA polymerase, mitochondrial (Q9NVV4). Polymerase that creates the 3’ poly(A) tail of mitochondrial transcripts. It is a selective cancer dependency (DepMap: 73.8% of cell lines).

The protein encoded by this gene is a member of the DNA polymerase type-B-like family. This enzyme synthesizes the 3’ poly(A) tail of mitochondrial transcripts and plays a role in replication-dependent histone mRNA degradation.

Source: NCBI Gene 55149 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 402 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 26
• Cancer dependency (DepMap): dependent in 73.8% of screened cell lines
• MANE Select transcript: NM_018109

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25532
Approved symbol	MTPAP
Name	mitochondrial poly(A) polymerase
Location	10p11.23
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10486, SPAX4, TENT6
Ensembl gene	ENSG00000107951
Ensembl biotype	protein_coding
OMIM	613669
Entrez	55149

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 10 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000263063, ENST00000417581, ENST00000421701, ENST00000471055, ENST00000488290, ENST00000904048, ENST00000904049, ENST00000912898, ENST00000912899, ENST00000958692, ENST00000958693, ENST00000958694

RefSeq mRNA: 1 — MANE Select: NM_018109 NM_018109

CCDS: CCDS7165

Canonical transcript exons

ENST00000263063 — 9 exons

Exon	Start	End
ENSE00000926134	30349119	30349278
ENSE00000997298	30309801	30313971
ENSE00003481181	30336803	30337027
ENSE00003482755	30322391	30322617
ENSE00003524406	30341468	30341640
ENSE00003597329	30316118	30316210
ENSE00003609095	30326424	30326635
ENSE00003642400	30315963	30316036
ENSE00003662839	30340226	30340450

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 97.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.3010 / max 2210.4566, expressed in 1782 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
108903	14.0122	1776
108902	0.2889	129
108904	0.1077	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	97.10	gold quality
secondary oocyte	CL:0000655	96.97	gold quality
gingival epithelium	UBERON:0001949	94.37	gold quality
cauda epididymis	UBERON:0004360	94.23	gold quality
parietal pleura	UBERON:0002400	94.16	gold quality
left testis	UBERON:0004533	94.06	gold quality
right testis	UBERON:0004534	94.02	gold quality
caput epididymis	UBERON:0004358	93.52	gold quality
visceral pleura	UBERON:0002401	93.29	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.27	gold quality
germinal epithelium of ovary	UBERON:0001304	92.99	gold quality
tibia	UBERON:0000979	92.83	gold quality
gingiva	UBERON:0001828	92.60	gold quality
pleura	UBERON:0000977	92.55	gold quality
endothelial cell	CL:0000115	92.52	gold quality
corpus epididymis	UBERON:0004359	92.44	gold quality
trabecular bone tissue	UBERON:0002483	92.35	gold quality
esophagus squamous epithelium	UBERON:0006920	92.26	gold quality
testis	UBERON:0000473	92.19	gold quality
oral cavity	UBERON:0000167	92.17	gold quality
mucosa of sigmoid colon	UBERON:0004993	91.54	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	91.46	gold quality
skin of hip	UBERON:0001554	91.31	gold quality
palpebral conjunctiva	UBERON:0001812	90.99	gold quality
biceps brachii	UBERON:0001507	90.84	gold quality
sperm	CL:0000019	90.78	gold quality
pons	UBERON:0000988	90.71	gold quality
colonic mucosa	UBERON:0000317	90.10	gold quality
penis	UBERON:0000989	89.78	gold quality
upper leg skin	UBERON:0004262	89.64	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.06

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

159 targeting MTPAP, 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-513A-5P	100.00	69.77	2465
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 73.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 9)

• Cloning of a human nuclear-encoded mitochondrial poly(A) polymerase (hmtPAP)that has a role in mitochondrial RNA processing. (PMID:15547249)
• Characterization of this marker shows that it is orthologous to the human gene KIAA1462 located on HSA10p11.23, where a major quantitative trait locus for morbid obesity has been reported. (PMID:16810331)
• show that dimerization is required for the catalytic activity of PAPD1 (PMID:21292163)
• Mutation of the MTPAP gene results in a cellular phenotype of increased DNA damage, reduced repair kinetics, increased cell death by apoptosis, and reduced clonogenic survival after exposure to ionizing radiation. (PMID:24651433)
• The polymerase activity of mtPAP is modulated by LRPPRC/SLIRP; N478D mtPAP mutation decreases its activity and the alteration in poly(A) length causes dysregulation of post-transcriptional expression and lack of respiratory chain complexes. (PMID:25008111)
• Mitochondrial poly(A) polymerase is able to add the discriminator adenosine to tRNATyr. (PMID:26354863)
• These results indicate that NDP52 and MTPAP form an autophagy receptor complex, which enhances autophagic elimination of damaged mitochondria. (PMID:30309841)
• Biallelic Mutations in MTPAP Associated with a Lethal Encephalopathy. (PMID:31779033)
• USP4 regulates TUT1 ubiquitination status in concert with SART3. (PMID:38310689)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	mtpap	ENSDARG00000076155
mus_musculus	Mtpap	ENSMUSG00000024234
rattus_norvegicus	Mtpap	ENSRNOG00000016578
drosophila_melanogaster	MTPAP	FBGN0024360
caenorhabditis_elegans	gld-2	WBGENE00001596
caenorhabditis_elegans		WBGENE00011131
caenorhabditis_elegans		WBGENE00019628
caenorhabditis_elegans		WBGENE00019629
caenorhabditis_elegans	T08B2.4	WBGENE00020345
caenorhabditis_elegans		WBGENE00021338
caenorhabditis_elegans		WBGENE00194706

Paralogs (4): TUT7 (ENSG00000083223), TUT4 (ENSG00000134744), TUT1 (ENSG00000149016), TENT2 (ENSG00000164329)

Protein

Protein identifiers

Poly(A) RNA polymerase, mitochondrial — Q9NVV4 (reviewed: Q9NVV4)

Alternative names: PAP-associated domain-containing protein 1, Polynucleotide adenylyltransferase, Terminal uridylyltransferase 1, mtPAP

All UniProt accessions (3): Q9NVV4, Q5T851, Q5T852

UniProt curated annotations — full annotation on UniProt →

Function. Polymerase that creates the 3’ poly(A) tail of mitochondrial transcripts. Can use all four nucleotides, but has higher activity with ATP and UTP (in vitro). Plays a role in replication-dependent histone mRNA degradation. May be involved in the terminal uridylation of mature histone mRNAs before their degradation is initiated. Might be responsible for the creation of some UAA stop codons which are not encoded in mtDNA.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm. Mitochondrion.

Tissue specificity. Ubiquitous, with stronger expression in tissues with high energy requirements: heart, brain, and skeletal muscle.

Disease relevance. Spastic ataxia 4, autosomal recessive (SPAX4) [MIM:613672] A slowly progressive neurodegenerative disease characterized by cerebellar ataxia, spastic paraparesis, dysarthria, and optic atrophy. The disease is caused by variants affecting the gene represented in this entry. MTPAP mutations result in a defect of mitochondrial mRNA maturation. Affected individuals exhibit a drastic decrease in poly(A) tail length of mitochondrial mRNA transcripts, including COX1 and RNA14.

Similarity. Belongs to the DNA polymerase type-B-like family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NVV4-1	1	yes
Q9NVV4-2	2

RefSeq proteins (1): NP_060579* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002058	PAP_assoc	Domain
IPR041252	RL	Domain
IPR043519	NT_sf	Homologous_superfamily
IPR054708	MTPAP-like_central	Domain

Pfam: PF03828, PF17797, PF22600

Enzyme classification (BRENDA):

• EC 2.7.7.19 — polynucleotide adenylyltransferase (BRENDA: 35 organisms, 181 substrates, 125 inhibitors, 114 Km, 53 kcat entries)

Substrate kinetics (BRENDA)

19 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.028–2.191	54
RNA (A)15	0.51–24.99	23
CTP	0.1036–4.7	7
(A)N	0.0468–0.711	5
OLIGO(A)14	0.0005–0.037	5
(A)15	0.0009–0.0053	3
GTP	0.055–0.062	2
OLIGO(A)18	0.0468–0.0642	2
OLIGO(A)N	0.01–0.3	2
2-AMINOPURINE RIBOSIDE TRIPHOSPHATE	0.0197	1
DATP	0.06	1
OLIGO(A)12	0.0004	1
OLIGO(A)17C	0.0263	1
OLIGOADENYLATE	0.2	1
POLY(A)N	0.0036	1

Catalyzed reactions (Rhea), 1 shown:

• RNA(n) + ATP = RNA(n)-3’-adenine ribonucleotide + diphosphate (RHEA:11332)

UniProt features (53 total): helix 17, strand 10, mutagenesis site 7, sequence variant 5, binding site 4, turn 3, sequence conflict 2, transit peptide 1, chain 1, domain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3PQ1	X-RAY DIFFRACTION	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NVV4-F1	83.16	0.69

Functional residue map

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

Ligand- & substrate-binding residues (4): 107–109; 241–242; 243; 245

Post-translational modifications (1): 90

Mutagenesis-validated functional residues (7):

Position	Phenotype
221–222	reduces dimerization.
230	reduced enzyme activity.
259–261	no effect on dimerization. loss of dimerization and of enzyme activity; when associated with 294-aaaa-297.
294–297	reduced dimerization. loss of dimerization and of enzyme activity; when associated with 259-aaa-261.
312	reduced enzyme activity.
325	loss of enzyme activity.
378	reduced enzyme activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9937008	Mitochondrial mRNA modification

MSigDB gene sets: 168 (showing top): GOBP_MACROMOLECULE_CATABOLIC_PROCESS, CHANDRAN_METASTASIS_DN, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, GOBP_MITOCHONDRIAL_RNA_PROCESSING, HP1SITEFACTOR_Q6, GOBP_MITOCHONDRIAL_RNA_METABOLIC_PROCESS, DODD_NASOPHARYNGEAL_CARCINOMA_UP, GOBP_HISTONE_MRNA_METABOLIC_PROCESS, GOBP_HISTONE_MRNA_CATABOLIC_PROCESS, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, REACTOME_METABOLISM_OF_RNA, GOCC_MITOCHONDRIAL_MATRIX, GOMF_MAGNESIUM_ION_BINDING, GOMF_ADENYLYLTRANSFERASE_ACTIVITY, GOMF_PROTEIN_DIMERIZATION_ACTIVITY

GO Biological Process (5): mitochondrial RNA 3’-end processing (GO:0000965), mRNA processing (GO:0006397), RNA 3’-end processing (GO:0031123), histone mRNA catabolic process (GO:0071044), mitochondrial mRNA polyadenylation (GO:0097222)

GO Molecular Function (13): magnesium ion binding (GO:0000287), UTP binding (GO:0002134), RNA binding (GO:0003723), ATP binding (GO:0005524), manganese ion binding (GO:0030145), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), poly(A) RNA polymerase activity (GO:1990817), nucleotide binding (GO:0000166), protein binding (GO:0005515), transferase activity (GO:0016740), nucleotidyltransferase activity (GO:0016779), metal ion binding (GO:0046872)

GO Cellular Component (4): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrial RNA processing	2
mitochondrion	2
RNA processing	2
cellular anatomical structure	2
RNA 3’-end processing	1
mRNA metabolic process	1
nuclear-transcribed mRNA catabolic process	1
histone mRNA metabolic process	1
metal ion binding	1
pyrimidine ribonucleotide binding	1
anion binding	1
nucleic acid binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transition metal ion binding	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
adenylyltransferase activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
transferase activity, transferring phosphorus-containing groups	1
cation binding	1
nuclear lumen	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1132 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MTPAP	PAPOLG	Q9BWT3	940
MTPAP	PAPOLA	P51003	936
MTPAP	PAPOLB	Q9NRJ5	934
MTPAP	SUPV3L1	Q8IYB8	824
MTPAP	TENT4B	Q8NDF8	798
MTPAP	SLIRP	Q9GZT3	742
MTPAP	PNPT1	Q8TCS8	709
MTPAP	LRPPRC	P42704	671
MTPAP	ELAC2	Q9BQ52	635
MTPAP	PDE12	Q6L8Q7	617
MTPAP	POLRMT	O00411	566
MTPAP	TENT4A	Q5XG87	563
MTPAP	GRSF1	Q12849	530
MTPAP	SEM1	Q6ZVN7	520
MTPAP	AFG3L2	Q9Y4W6	519

IntAct

95 interactions, top by confidence:

A	B	Type	Score
TBK1	TBKBP1	psi-mi:“MI:0914”(association)	0.860
DYNLL1	BLTP3B	psi-mi:“MI:0914”(association)	0.730
ARPC5	ARPC3	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
DYNLL2	BLTP3B	psi-mi:“MI:0914”(association)	0.640
CALCOCO2	TBKBP1	psi-mi:“MI:0914”(association)	0.640
CALCOCO2	AZI2	psi-mi:“MI:0914”(association)	0.640
MTPAP	MTPAP	psi-mi:“MI:0407”(direct interaction)	0.620
MTPAP	CALCOCO2	psi-mi:“MI:0915”(physical association)	0.620
CD79A	METTL15	psi-mi:“MI:0914”(association)	0.530
EMILIN1	METTL15	psi-mi:“MI:0914”(association)	0.530
YBEY	NME4	psi-mi:“MI:0914”(association)	0.530
LRP1	NME4	psi-mi:“MI:0914”(association)	0.530
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530
GEMIN7	GEMIN2	psi-mi:“MI:0914”(association)	0.530
RRP8	MAGEB2	psi-mi:“MI:0914”(association)	0.530
LIN28B	ELAVL2	psi-mi:“MI:0914”(association)	0.530
PNMA2	CCDC85C	psi-mi:“MI:0914”(association)	0.530
DYNLL1	SHMT2	psi-mi:“MI:0914”(association)	0.510
DYNLL2	SHMT2	psi-mi:“MI:0914”(association)	0.510

BioGRID (187): MTPAP (Affinity Capture-MS), MTPAP (Affinity Capture-MS), MTPAP (Affinity Capture-MS), MTPAP (Affinity Capture-MS), MTPAP (Affinity Capture-MS), MTPAP (Affinity Capture-MS), MTPAP (Affinity Capture-MS), MTPAP (Affinity Capture-MS), MTPAP (Affinity Capture-MS), MTPAP (Affinity Capture-MS), MTPAP (Affinity Capture-MS), MTPAP (Affinity Capture-MS), MTPAP (Affinity Capture-MS), MTPAP (Affinity Capture-MS), MTPAP (Affinity Capture-MS)

ESM2 similar proteins: A0A2R8QPS5, A1A5P5, A4IG61, A6H8I2, A9JTS5, B5DF07, F1M386, F1MSG6, G5EDB9, M9MRI4, O46102, P0C0R5, P97874, Q01820, Q0VFA3, Q17QN2, Q2I6J0, Q2KI13, Q2KI89, Q32PH0, Q3U0M1, Q3U213, Q4KMD7, Q5RAR6, Q5SNQ7, Q641A1, Q68F70, Q6DFA8, Q6P6R7, Q6ZPE2, Q7T2D0, Q8CHG7, Q8CIM8, Q8JZY4, Q8K337, Q8R1F6, Q8VCZ6, Q8VD65, Q91YN0, Q96GM8

Diamond homologs: A9JTS5, D2HS90, O13833, Q1JPD6, Q3MHT4, Q4KMD7, Q641A1, Q8R3F9, Q9D0D3, Q9H6E5, Q9NVV4, Q9UT49, O13798, Q5U315, Q91YI6, Q9VD44, O46102, Q9VYS4, O74326, P07909, P51989, P51990, Q96EP5, Q98SJ2, Q9JII5, B2RX14, O17087, O64642, Q0VFA3, Q2HJ44, Q503I9, Q5TAX3, Q6DFA8, Q6PIY7, Q7KVS9, Q5VYS8, Q5XET5

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 121 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
SARS-CoV-2 modulates host translation machinery	5	15.3×	3e-03
SARS-CoV-1-host interactions	6	14.4×	1e-03
Leishmania infection	5	11.2×	7e-03
Parasitic Infection Pathways	5	11.2×	7e-03
Signaling by ALK fusions and activated point mutants	5	10.3×	7e-03
SARS-CoV-1 Infection	5	9.8×	8e-03
Infectious disease	13	4.4×	1e-03
Innate Immune System	11	3.8×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	174
Likely benign	154
Benign	44

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
18391	NM_018109.4(MTPAP):c.1432A>G (p.Asn478Asp)	Pathogenic
1027494	NM_018109.4(MTPAP):c.1464A>C (p.Lys488Asn)	Likely pathogenic

SpliceAI

1991 predictions. Top by Δscore:

Variant	Effect	Δscore
10:30316032:TAATT:T	acceptor_gain	1.0000
10:30316034:ATT:A	acceptor_gain	1.0000
10:30316035:TT:T	acceptor_gain	1.0000
10:30316035:TTCT:T	acceptor_loss	1.0000
10:30316036:TCT:T	acceptor_loss	1.0000
10:30316037:C:CC	acceptor_gain	1.0000
10:30316037:CTGT:C	acceptor_loss	1.0000
10:30316038:T:C	acceptor_loss	1.0000
10:30316113:CTTA:C	donor_loss	1.0000
10:30316114:TTA:T	donor_loss	1.0000
10:30316115:TACCT:T	donor_loss	1.0000
10:30316116:ACCTA:A	donor_loss	1.0000
10:30316117:C:CT	donor_loss	1.0000
10:30316211:C:CC	acceptor_gain	1.0000
10:30316212:T:C	acceptor_gain	1.0000
10:30326418:TCATA:T	donor_loss	1.0000
10:30326419:CATA:C	donor_loss	1.0000
10:30326420:ATAC:A	donor_loss	1.0000
10:30326421:TA:T	donor_loss	1.0000
10:30326422:A:AG	donor_loss	1.0000
10:30326423:C:CT	donor_loss	1.0000
10:30326549:T:A	donor_gain	1.0000
10:30326633:GATC:G	acceptor_loss	1.0000
10:30326636:C:CA	acceptor_loss	1.0000
10:30326636:C:CC	acceptor_gain	1.0000
10:30336798:CTTA:C	donor_loss	1.0000
10:30336799:TTA:T	donor_loss	1.0000
10:30336800:TAC:T	donor_loss	1.0000
10:30336801:A:AC	donor_gain	1.0000
10:30336801:AC:A	donor_gain	1.0000

AlphaMissense

3822 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:30313897:G:C	S487R	0.998
10:30313897:G:T	S487R	0.998
10:30313899:T:G	S487R	0.998
10:30322532:A:G	W360R	0.997
10:30322532:A:T	W360R	0.997
10:30322537:C:G	R358P	0.997
10:30336893:A:C	F230L	0.997
10:30336893:A:T	F230L	0.997
10:30336895:A:G	F230L	0.997
10:30322528:G:T	A361D	0.996
10:30326442:T:C	D325G	0.996
10:30336849:T:A	D245V	0.996
10:30336849:T:G	D245A	0.996
10:30322529:C:G	A361P	0.995
10:30322602:A:C	S336R	0.995
10:30322602:A:T	S336R	0.995
10:30322604:T:G	S336R	0.995
10:30326441:A:C	D325E	0.995
10:30326441:A:T	D325E	0.995
10:30326442:T:G	D325A	0.995
10:30326446:A:G	C324R	0.995
10:30326502:A:G	I305T	0.995
10:30336848:G:C	D245E	0.995
10:30336848:G:T	D245E	0.995
10:30336855:T:A	D243V	0.995
10:30336855:T:G	D243A	0.995
10:30336891:C:T	G231D	0.995
10:30341565:A:T	V78D	0.995
10:30313903:G:C	N485K	0.994
10:30313903:G:T	N485K	0.994

dbSNP variants (sampled 300 via entrez): RS1000016453 (10:30327458 T>C), RS1000047249 (10:30331429 A>C), RS1000074678 (10:30333052 C>A,T), RS1000102699 (10:30315521 A>G), RS1000117685 (10:30342911 G>GT), RS1000119465 (10:30347147 T>C), RS1000228100 (10:30347906 A>C,G), RS1000295046 (10:30344602 C>T), RS1000325282 (10:30327770 T>C), RS1000341005 (10:30312895 T>C), RS1000389571 (10:30344171 C>T), RS1000445497 (10:30313707 T>C,G), RS1000640161 (10:30310717 T>C), RS1000703555 (10:30316822 G>A), RS1000719661 (10:30341885 T>A,C)

Disease associations

OMIM: gene MIM:613669 | disease phenotypes: MIM:108600, MIM:613672

GenCC curated gene-disease

Disease	Classification	Inheritance
spastic ataxia 4	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR

Mondo (3): spastic ataxia (MONDO:0017845), spastic ataxia 4 (MONDO:0013354), inherited retinal dystrophy (MONDO:0019118)

Orphanet (3): Spastic ataxia (Orphanet:316226), Autosomal recessive spastic ataxia-optic atrophy-dysarthria syndrome (Orphanet:254343), OBSOLETE: Inherited retinal disorder (Orphanet:71862)

HPO phenotypes

26 total (27 of 26 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000182	Movement abnormality of the tongue
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000712	Emotional lability
HP:0000750	Delayed speech and language development
HP:0001260	Dysarthria
HP:0001265	Hyporeflexia
HP:0001270	Motor delay
HP:0001336	Myoclonus
HP:0001347	Hyperreflexia
HP:0002066	Gait ataxia
HP:0002070	Limb ataxia
HP:0002073	Progressive cerebellar ataxia
HP:0002313	Spastic paraparesis
HP:0002359	Frequent falls
HP:0002497	Spastic ataxia
HP:0003487	Babinski sign
HP:0003593	Infantile onset
HP:0003677	Slowly progressive
HP:0006895	Lower limb hypertonia
HP:0007083	Hyperactive patellar reflex
HP:0007240	Progressive gait ataxia
HP:0009072	Decreased Achilles reflex
HP:0031936	Delayed ability to walk
HP:0200049	Upper limb hypertonia
HP:0000556	Retinal dystrophy

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005352_20	Paclitaxel disposition in epithelial ovarian cancer	6.000000e-06

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D058499	Retinal Dystrophies	C11.768.585.658
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

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression, affects methylation, decreases expression	3
Benzo(a)pyrene	affects methylation	2
Formaldehyde	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Valproic Acid	affects expression, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	increases expression	1
bisphenol A	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
jinfukang	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Sunitinib	increases expression	1
Zoledronic Acid	increases expression	1
Vorinostat	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Ivermectin	decreases expression	1
Manganese	increases expression, affects cotreatment, increases abundance	1
Mercuric Chloride	increases expression	1
Ozone	increases abundance, affects expression	1
Plant Extracts	affects cotreatment, increases expression	1
Ribonucleotides	affects binding	1
Testosterone	decreases expression	1
Thimerosal	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT04297891	Not specified	UNKNOWN	Phenotypes, Biomarkers and Pathophysiology in Spastic Ataxias
NCT04855045	PHASE2/PHASE3	UNKNOWN	An Open-label, Dose Escalation and Double-masked, Randomized, Controlled Trial Evaluating Safety and Tolerability of Sepofarsen in Children (<8 Years of Age) With LCA10 Caused by Mutations in the CEP290 Gene.
NCT03872479	PHASE1/PHASE2	UNKNOWN	Single Ascending Dose Study in Participants With LCA10
NCT04123626	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate the Safety and Tolerability of QR-1123 in Subjects With Autosomal Dominant Retinitis Pigmentosa Due to the P23H Mutation in the RHO Gene
NCT04545736	PHASE1/PHASE2	RECRUITING	Oral Metformin for Treatment of ABCA4 Retinopathy
NCT06212297	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Fellow-eye Study (FE) of LX101 in Subjects With Inherited Retinal Dystrophy
NCT06852963	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Repeat-Dose, Open-Label, Two Arm Safety and Efficacy Study of Two Doses of VP-001 Administered Intravitreally in Participants With Confirmed PRPF31 Mutation-Associated Retinal Dystrophy, Including Participants Previously Treated With VP001
NCT07177196	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Personalized Antisense Oligonucleotide Therapy for a Single Participant With PRPH2 Mutation Associated With Retinal Dystrophy
NCT07063030	EARLY_PHASE1	RECRUITING	A Study of LX107 Gene Therapy in AIPL1-IRD Patients
NCT01546181	Not specified	COMPLETED	Retinal Imaging by Adaptive Optics in Healthy Eyes and During Retinal and General Diseases
NCT01876147	Not specified	COMPLETED	Visual and Functional Assessment in Low Vision Patients
NCT01920867	Not specified	UNKNOWN	Stem Cell Ophthalmology Treatment Study
NCT02014389	Not specified	RECRUITING	Evaluation of Objective Perimetry Using Chromatic Multifocal Pupillometer
NCT02983305	Not specified	COMPLETED	Optical Head-Mounted Display Technology for Low Vision Rehabilitation
NCT03592017	Not specified	COMPLETED	Performance of Long-wavelength Autofluorescence Imaging
NCT03662386	Not specified	TERMINATED	Prospective Analysis of Genotype-phenotype Correlations Observed in a Large Cohort of Patients With Hereditary Retinal Dystrophies - GEPHIRD
NCT03691168	Not specified	UNKNOWN	Multi-center Observation of the Natural Course of Inherited Retinal Dystrophies
NCT03843840	Not specified	COMPLETED	Dual Wavelength OCT
NCT03853252	Not specified	COMPLETED	iPS Cells of Patients for Models of Retinal Dystrophies
NCT05130385	Not specified	UNKNOWN	High Resolution Optical Coherence Tomography
NCT05294978	Not specified	RECRUITING	EyeConic: Qualification for Cone-Optogenetics
NCT05573984	Not specified	ACTIVE_NOT_RECRUITING	Natural History of PRPF31 Mutation-Associated Retinal Dystrophy
NCT05793515	Not specified	COMPLETED	Mechanisms of Inherited Retinal Dystrophies Using Whole Genome Sequencing and in Vitro and in Vivo Models
NCT05820100	Not specified	COMPLETED	Observational Study to Assess the Reliability and Validity of the MLYMT and MLSDT
NCT05976139	Not specified	RECRUITING	Micropulsed Laser in Patients With Macular Oedema in Retinal Dystrophies
NCT06162585	Not specified	ACTIVE_NOT_RECRUITING	Non-Interventional Long Term Follow-up Study of Participants Previously Enrolled in the RESTORE Study
NCT06177977	Not specified	RECRUITING	SS-HH-OCT as a Novel Diagnostic Modality for Early-Onset Retinal Dystrophies (EORDs)
NCT06375239	Not specified	RECRUITING	Observational Study to Assess Endpoint Operational Feasibility & Measurement Properties in Patients with Retinal Degeneration
NCT06908161	Not specified	NOT_YET_RECRUITING	Functional Assessments in Vision Impairment
NCT07085533	Not specified	RECRUITING	Natural History Study of Inherited Retinal Diseases
NCT07502664	Not specified	RECRUITING	Development and Evaluation of Functional Visual Field and Navigation Endpoints in Moderate to Profound Inherited Retinal Disease (DEFINE-IRD)