PMPCA

Summary

PMPCA (peptidase, mitochondrial processing subunit alpha, HGNC:18667) is a protein-coding gene on chromosome 9q34.3, encoding Mitochondrial-processing peptidase subunit alpha (Q10713). Substrate recognition and binding subunit of the essential mitochondrial processing protease (MPP), which cleaves the mitochondrial sequence off newly imported precursors proteins. It is a common-essential gene (DepMap: required in 99.2% of cancer cell lines).

The protein encoded by this gene is found in the mitochondrion, where it represents the alpha subunit of a proteolytic heterodimer. This heterodimer is responsible for cleaving the transit peptide from nuclear-encoded mitochondrial proteins. Defects in this gene are a cause of spinocerebellar ataxia, autosomal recessive 2.

Source: NCBI Gene 23203 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 24
• Clinical variants (ClinVar): 1,179 total — 42 pathogenic, 36 likely-pathogenic
• Phenotypes (HPO): 147
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.2% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_015160

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18667
Approved symbol	PMPCA
Name	peptidase, mitochondrial processing subunit alpha
Location	9q34.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0123, Alpha-MPP, MAS2
Ensembl gene	ENSG00000165688
Ensembl biotype	protein_coding
OMIM	613036
Entrez	23203

Gene structure

Transcript identifiers

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

ENST00000371717, ENST00000371720, ENST00000399219, ENST00000444897, ENST00000462616, ENST00000610649, ENST00000612553, ENST00000614402, ENST00000619192, ENST00000620412, ENST00000620895, ENST00000622209, ENST00000706227, ENST00000706228, ENST00000706375, ENST00000706376, ENST00000706377, ENST00000706378, ENST00000706379, ENST00000706380, ENST00000706381, ENST00000706382, ENST00000706383, ENST00000706384, ENST00000706385, ENST00000706386, ENST00000706387, ENST00000706388, ENST00000706389, ENST00000706390, ENST00000873467, ENST00000914545, ENST00000914546, ENST00000914547, ENST00000965378, ENST00000965379, ENST00000965380

RefSeq mRNA: 3 — MANE Select: NM_015160 NM_001282944, NM_001282946, NM_015160

CCDS: CCDS35180

Canonical transcript exons

ENST00000371717 — 13 exons

Exon	Start	End
ENSE00001095491	136421832	136421976
ENSE00001604645	136414553	136414647
ENSE00001644649	136416291	136416391
ENSE00001788158	136416951	136417214
ENSE00001788538	136419044	136419106
ENSE00003471276	136411997	136412199
ENSE00003499480	136418828	136418918
ENSE00003515706	136418017	136418109
ENSE00003561156	136418555	136418673
ENSE00003733817	136412810	136412892
ENSE00003754870	136412490	136412569
ENSE00003995732	136410658	136410739
ENSE00003995743	136423095	136423761

Expression profiles

Bgee: expression breadth ubiquitous, 276 present calls, max score 96.34.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 41.0183 / max 240.8901, expressed in 1823 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
99500	37.8983	1823
103159	7.6685	1737
99499	3.0186	1571
99502	0.0975	7
99501	0.0039	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	96.34	gold quality
adrenal tissue	UBERON:0018303	96.08	gold quality
apex of heart	UBERON:0002098	96.00	gold quality
right adrenal gland	UBERON:0001233	95.38	gold quality
heart left ventricle	UBERON:0002084	95.33	gold quality
right adrenal gland cortex	UBERON:0035827	95.31	gold quality
left adrenal gland	UBERON:0001234	95.29	gold quality
cardiac ventricle	UBERON:0002082	95.15	gold quality
left adrenal gland cortex	UBERON:0035825	95.07	gold quality
gastrocnemius	UBERON:0001388	94.83	gold quality
muscle of leg	UBERON:0001383	94.54	gold quality
adrenal gland	UBERON:0002369	94.49	gold quality
adrenal cortex	UBERON:0001235	94.42	gold quality
right atrium auricular region	UBERON:0006631	94.33	gold quality
heart	UBERON:0000948	93.93	gold quality
liver	UBERON:0002107	93.87	gold quality
cardiac atrium	UBERON:0002081	93.68	gold quality
stromal cell of endometrium	CL:0002255	93.63	gold quality
ventricular zone	UBERON:0003053	93.57	gold quality
adenohypophysis	UBERON:0002196	93.54	gold quality
triceps brachii	UBERON:0001509	93.52	gold quality
right testis	UBERON:0004534	93.51	gold quality
left testis	UBERON:0004533	93.50	gold quality
muscle organ	UBERON:0001630	93.48	gold quality
mucosa of transverse colon	UBERON:0004991	93.44	gold quality
body of stomach	UBERON:0001161	93.41	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.41	gold quality
skin of abdomen	UBERON:0001416	93.18	gold quality
skin of leg	UBERON:0001511	93.13	gold quality
pituitary gland	UBERON:0000007	93.05	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.73
E-MTAB-7606	no	950.85
E-GEOD-124858	no	109.90

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

7 targeting PMPCA, 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-4267	99.96	66.53	2368
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-7702	99.06	65.95	698
HSA-MIR-7113-5P	97.88	67.33	1735
HSA-MIR-6753-5P	94.70	64.08	470
HSA-MIR-6774-3P	89.14	65.20	68

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 99.2% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 5)

• OxLDL triggers retrograde translocation of arginase2 in aortic endothelial cells via ROCK and mitochondrial processing peptidase. (PMID:24903103)
• study represents the first time that defects in PMPCA and mitochondrial processing peptidase have been described in association with a disease phenotype in humans. (PMID:25808372)
• Functional coupling of presequence processing and degradation in human mitochondria. (PMID:32491259)
• A severe form of autosomal recessive spinocerebellar ataxia associated with novel PMPCA variants. (PMID:33272776)
• Next-Generation Sequencing Identifies Novel PMPCA Variants in Patients with Late-Onset Dominant Optic Atrophy. (PMID:35885985)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pmpca	ENSDARG00000102607
mus_musculus	Pmpca	ENSMUSG00000026926
rattus_norvegicus	Pmpca	ENSRNOG00000026775
drosophila_melanogaster	CG8728	FBGN0033235
caenorhabditis_elegans	mppa-1	WBGENE00022159

Paralogs (6): UQCRC1 (ENSG00000010256), NRDC (ENSG00000078618), PMPCB (ENSG00000105819), PITRM1 (ENSG00000107959), IDE (ENSG00000119912), UQCRC2 (ENSG00000140740)

Protein

Protein identifiers

Mitochondrial-processing peptidase subunit alpha — Q10713 (reviewed: Q10713)

Alternative names: Alpha-MPP, Inactive zinc metalloprotease alpha, P-55

All UniProt accessions (10): A0A994J5B5, A0A994J5C0, A0A994J5K1, A0A994J5K6, A0A994J5X6, A0A994J7S6, A0A9H4AR20, A0A9L9PWU5, Q10713, Q5SXN9

UniProt curated annotations — full annotation on UniProt →

Function. Substrate recognition and binding subunit of the essential mitochondrial processing protease (MPP), which cleaves the mitochondrial sequence off newly imported precursors proteins.

Subunit / interactions. Heterodimer of PMPCA (alpha) and PMPCB (beta) subunits, forming the mitochondrial processing protease (MPP) in which PMPCA is involved in substrate recognition and binding and PMPCB is the catalytic subunit.

Subcellular location. Mitochondrion matrix. Mitochondrion inner membrane.

Tissue specificity. Ubiquitously expressed with highest expression in fetal tissues and adult brain, cerebellum and cerebellar vermis.

Disease relevance. Spinocerebellar ataxia, autosomal recessive, 2 (SCAR2) [MIM:213200] A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR2 is characterized by onset of impaired motor development and ataxic gait in early childhood. Additional features often include loss of fine motor skills, dysarthria, nystagmus, cerebellar signs, and delayed cognitive development with intellectual disability. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the peptidase M16 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q10713-1	1	yes
Q10713-2	2

RefSeq proteins (3): NP_001269873, NP_001269875, NP_055975* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001431	Pept_M16_Zn_BS	Binding_site
IPR007863	Peptidase_M16_C	Domain
IPR011249	Metalloenz_LuxS/M16	Homologous_superfamily
IPR011765	Pept_M16_N	Domain
IPR050361	MPP/UQCRC_Complex	Family

Pfam: PF00675, PF05193

Enzyme classification (BRENDA):

• EC 3.4.24.64 — mitochondrial processing peptidase (BRENDA: 22 organisms, 232 substrates, 66 inhibitors, 43 Km, 30 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
MDH1-21	0.0001–0.0009	11
ARAARAARAFTSSA	0.0103–0.015	2
ARAARAARAYGSTA	0.0098–0.0101	2
ABZ-FQTKVAAK(DNP)-NH2	0.0034	1
ABZ-FRSGQPLQNKVQLQ-ED(DNP)	0.0009	1
ABZ-FSSKTTVK(DNP)-NH2	0.0013	1
ABZ-IKQSSLLK(DNP)-NH2	0.0011	1
ABZ-MTAALKTK(DNP)-NH2	0.0042	1
ABZ-NLMKKSTK(DNP)-NH2	0.0013	1
ABZ-QPLANKVQ-ED(DNP)	0.0051	1
ABZ-QPLQAKVQ-ED(DNP)	0.0032	1
ABZ-QPLQNKVQ-ED(DNP)	0.0029	1
ABZ-TTKLKAAK(DNP)-NH2	0.0008	1
ABZ-VAAQTKTK(DNP)-NH2	0.01	1
ABZ-VISSRLEK(DNP)-NH2	0.0019	1

UniProt features (12 total): sequence variant 4, sequence conflict 2, modified residue 2, splice variant 2, transit peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q10713-F1	88.46	0.77

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 (2): 64, 299

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1268020	Mitochondrial protein import
R-HSA-8949664	Processing of SMDT1
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-382551	Transport of small molecules
R-HSA-392499	Metabolism of proteins
R-HSA-8949215	Mitochondrial calcium ion transport
R-HSA-9609507	Protein localization

MSigDB gene sets: 566 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_LIPID_MODIFICATION, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_PHOSPHATIDYLINOSITOL_METABOLIC_PROCESS, MORF_MSH3, GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_PROTEIN_LOCALIZATION_TO_CILIUM, GOBP_PHOSPHOLIPID_DEPHOSPHORYLATION, MORF_BRCA1, MORF_ATRX, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_PROTEIN_TARGETING, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOCC_RUFFLE, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE

GO Biological Process (3): obsolete protein processing involved in protein targeting to mitochondrion (GO:0006627), protein processing (GO:0016485), proteolysis (GO:0006508)

GO Molecular Function (3): metalloendopeptidase activity (GO:0004222), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (6): obsolete extracellular space (GO:0005615), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), mitochondrial processing peptidase complex (GO:0017087), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Protein localization	1
Mitochondrial calcium ion transport	1
Metabolism of proteins	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
proteolysis	1
protein maturation	1
protein metabolic process	1
endopeptidase activity	1
metallopeptidase activity	1
cation binding	1
binding	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrion	1
intracellular organelle lumen	1
mitochondrial matrix	1
mitochondrial protein-containing complex	1
endopeptidase complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

3062 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PMPCA	PMPCB	O75439	947
PMPCA	CETN2	P41208	816
PMPCA	IDE	P14735	702
PMPCA	MIPEP	Q99797	667
PMPCA	XPNPEP3	Q9NQH7	646
PMPCA	SNAPC4	Q5SXM2	608
PMPCA	SAMM50	Q9Y512	582
PMPCA	IMMP2L	Q96T52	575
PMPCA	AFG3L2	Q9Y4W6	572
PMPCA	PDGFRA	P16234	549
PMPCA	FXN	Q16595	528
PMPCA	LONP1	P36776	511
PMPCA	SPG7	Q9UQ90	506
PMPCA	METTL15	A6NJ78	504
PMPCA	TIMM17A	Q99595	495

IntAct

152 interactions, top by confidence:

A	B	Type	Score
SOST	LRP6	psi-mi:“MI:0914”(association)	0.890
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
COQ8A	COQ9	psi-mi:“MI:0914”(association)	0.670
MRPS30	GTPBP10	psi-mi:“MI:0914”(association)	0.640
NDUFAF4	NDUFS8	psi-mi:“MI:0914”(association)	0.640
	PMPCB	psi-mi:“MI:0914”(association)	0.640
CCDC120	AIP	psi-mi:“MI:0914”(association)	0.640
PMPCA	H1-1	psi-mi:“MI:0915”(physical association)	0.560
ZNF76	PMPCA	psi-mi:“MI:0915”(physical association)	0.560
ODAPH	TCAF2	psi-mi:“MI:0914”(association)	0.530
NPPA	A2ML1	psi-mi:“MI:0914”(association)	0.530
SPINK2	STRN	psi-mi:“MI:0914”(association)	0.530
DEFB1	NMT2	psi-mi:“MI:0914”(association)	0.530
PMPCA	CLUH	psi-mi:“MI:0914”(association)	0.530
MRM3	NDUFS6	psi-mi:“MI:0914”(association)	0.530
MTG2	HSPD1	psi-mi:“MI:0914”(association)	0.530
	PMPCB	psi-mi:“MI:0914”(association)	0.530
PMPCA	PMPCB	psi-mi:“MI:0914”(association)	0.530
MMAB	PMPCB	psi-mi:“MI:0914”(association)	0.530

BioGRID (465): PMPCA (Affinity Capture-MS), PMPCA (Affinity Capture-MS), PMPCA (Affinity Capture-MS), PMPCA (Affinity Capture-MS), PMPCA (Co-fractionation), PMPCA (Co-fractionation), PMPCB (Co-fractionation), UQCRC1 (Co-fractionation), PMPCA (Affinity Capture-MS), PMPCA (Affinity Capture-MS), PMPCA (Affinity Capture-MS), PMPCA (Affinity Capture-MS), PMPCA (Affinity Capture-MS), PMPCA (Affinity Capture-MS), PMPCA (Affinity Capture-MS)

ESM2 similar proteins: A9X1D0, B0VX69, B1MTJ4, B2KI88, B4F753, B5FW36, B7ZUF3, C1FXW2, E2RBS6, E9PTA2, G3V6U9, O43847, O54804, O94759, O95453, O95803, P11926, P20069, P27117, P47245, Q0P5M8, Q10713, Q13507, Q4R4U1, Q4R766, Q5R4H6, Q5R513, Q5R5F8, Q5RC51, Q5U4X8, Q61143, Q6AYT7, Q6GQK9, Q7SXS7, Q7TT45, Q86TU7, Q8BHG1, Q8N2K0, Q91WC0, Q91YD4

Diamond homologs: O04308, O94745, P10507, P11913, P11914, P20069, P22695, P23004, P23955, P29677, P32551, P97997, Q0P5M8, Q10713, Q42290, Q5R513, Q9DB77, Q9DC61, Q9P7X1, Q9ZU25, B8B0E2, O32965, O75439, P05458, P0A5S9, P31800, P31930, P43264, P86201, P98080, P9WHT4, P9WHT5, Q00302, Q03346, Q23295, Q3SZ71, Q40983, Q4UML9, Q4W6B5, Q5REK3

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 132 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
Mitochondrial protein import	7	12.9×	6e-05
Complex I biogenesis	7	12.7×	6e-05
Respiratory electron transport	9	9.4×	6e-05
Aerobic respiration and respiratory electron transport	9	8.8×	6e-05
Mitochondrial ribosome-associated quality control	6	8.1×	4e-03
Mitochondrial protein degradation	6	7.5×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
ubiquinone biosynthetic process	6	48.0×	1e-06
mitochondrial electron transport, NADH to ubiquinone	7	21.4×	1e-05
mitochondrial respiratory chain complex I assembly	6	21.1×	7e-05
proton motive force-driven mitochondrial ATP synthesis	7	15.8×	7e-05
aerobic respiration	6	12.7×	8e-04
mitochondrion organization	8	10.4×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

1179 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	42
Likely pathogenic	36
Uncertain significance	515
Likely benign	402
Benign	65

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069370	NM_019892.6(INPP5E):c.1629C>G (p.Tyr543Ter)	Pathogenic
1070977	NM_019892.6(INPP5E):c.1253_1256del (p.Phe418fs)	Pathogenic
1075353	NM_019892.6(INPP5E):c.1795C>T (p.Arg599Ter)	Pathogenic
1256053	NM_015160.3(PMPCA):c.1408+1G>A	Pathogenic
1420962	NM_019892.6(INPP5E):c.1367A>C (p.Asn456Thr)	Pathogenic
1444511	NM_019892.6(INPP5E):c.1726T>G (p.Cys576Gly)	Pathogenic
1452581	NM_019892.6(INPP5E):c.166del (p.Ala56fs)	Pathogenic
1458128	NM_019892.6(INPP5E):c.15_16del (p.Asn7fs)	Pathogenic
1805447	NM_019892.6(INPP5E):c.226dup (p.Ala76fs)	Pathogenic
1930282	NM_019892.6(INPP5E):c.781dup (p.Ala261fs)	Pathogenic
2013249	NM_015160.3(PMPCA):c.1221del (p.Ile408fs)	Pathogenic
2020468	NM_019892.6(INPP5E):c.1324_1327dup (p.Val443fs)	Pathogenic
2032908	NM_019892.6(INPP5E):c.1103del (p.His368fs)	Pathogenic
2048453	NM_019892.6(INPP5E):c.1761_1763dup (p.Tyr588Ter)	Pathogenic
2158999	NM_019892.6(INPP5E):c.931C>T (p.Gln311Ter)	Pathogenic
217655	NM_019892.6(INPP5E):c.1064C>T (p.Thr355Met)	Pathogenic
217658	NM_019892.6(INPP5E):c.1897_1898del (p.Gln633fs)	Pathogenic
217662	NM_019892.6(INPP5E):c.944C>T (p.Pro315Leu)	Pathogenic
217664	NM_019892.6(INPP5E):c.1249T>C (p.Ser417Pro)	Pathogenic
2198850	NM_019892.6(INPP5E):c.925C>T (p.Gln309Ter)	Pathogenic
221552	NM_015160.3(PMPCA):c.1129G>A (p.Ala377Thr)	Pathogenic
221553	NM_015160.3(PMPCA):c.1066G>A (p.Gly356Ser)	Pathogenic
221564	NM_015160.3(PMPCA):c.287C>T (p.Ser96Leu)	Pathogenic
221565	NM_015160.3(PMPCA):c.1543G>A (p.Gly515Arg)	Pathogenic
2701602	NM_019892.6(INPP5E):c.1888C>T (p.Gln630Ter)	Pathogenic
2722122	NM_015160.3(PMPCA):c.100del (p.Ser34fs)	Pathogenic
279812	NM_019892.6(INPP5E):c.490dup (p.Val164fs)	Pathogenic
3245352	NC_000009.11:g.(?139304522)(139309119_?)del	Pathogenic
3249361	NM_019892.6(INPP5E):c.964del (p.Leu322fs)	Pathogenic
3720920	NM_019892.6(INPP5E):c.1426G>A (p.Gly476Arg)	Pathogenic

SpliceAI

4400 predictions. Top by Δscore:

Variant	Effect	Δscore
9:136411991:TTTTA:T	acceptor_loss	1.0000
9:136411992:TTTA:T	acceptor_loss	1.0000
9:136411994:TA:T	acceptor_loss	1.0000
9:136411995:AGGTT:A	acceptor_loss	1.0000
9:136411996:GGTTT:G	acceptor_gain	1.0000
9:136412195:AGGAA:A	donor_gain	1.0000
9:136412196:GGAA:G	donor_gain	1.0000
9:136412196:GGAAG:G	donor_gain	1.0000
9:136412197:G:GT	donor_gain	1.0000
9:136412197:GAA:G	donor_gain	1.0000
9:136412198:AA:A	donor_gain	1.0000
9:136412198:AAG:A	donor_loss	1.0000
9:136412199:AG:A	donor_loss	1.0000
9:136412200:G:GG	donor_gain	1.0000
9:136412201:T:A	donor_loss	1.0000
9:136412488:A:AG	acceptor_gain	1.0000
9:136412489:G:GA	acceptor_gain	1.0000
9:136412489:GTT:G	acceptor_gain	1.0000
9:136412489:GTTC:G	acceptor_gain	1.0000
9:136412489:GTTCT:G	acceptor_gain	1.0000
9:136412566:TTCGG:T	donor_loss	1.0000
9:136412567:TCGG:T	donor_loss	1.0000
9:136412569:GGT:G	donor_loss	1.0000
9:136412570:G:A	donor_loss	1.0000
9:136412570:G:GG	donor_gain	1.0000
9:136412571:T:A	donor_loss	1.0000
9:136412581:GTTTT:G	donor_gain	1.0000
9:136412808:A:AG	acceptor_gain	1.0000
9:136412809:G:GG	acceptor_gain	1.0000
9:136412809:GT:G	acceptor_gain	1.0000

AlphaMissense

3406 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:136418612:T:C	F350L	1.000
9:136418614:C:A	F350L	1.000
9:136418614:C:G	F350L	1.000
9:136418630:G:C	G356R	1.000
9:136418631:G:A	G356D	1.000
9:136418635:G:C	K357N	1.000
9:136418635:G:T	K357N	1.000
9:136418636:G:C	G358R	1.000
9:136421860:T:C	L431P	1.000
9:136416955:C:A	A213D	0.999
9:136418087:G:A	G323E	0.999
9:136418095:A:C	S326R	0.999
9:136418097:C:A	S326R	0.999
9:136418097:C:G	S326R	0.999
9:136418597:G:C	G345R	0.999
9:136418598:G:A	G345D	0.999
9:136418601:G:A	G346E	0.999
9:136418604:G:A	G347D	0.999
9:136418612:T:A	F350I	0.999
9:136418612:T:G	F350V	0.999
9:136418613:T:C	F350S	0.999
9:136418613:T:G	F350C	0.999
9:136418615:T:C	S351P	0.999
9:136418619:C:A	A352D	0.999
9:136418621:G:C	G353R	0.999
9:136418622:G:A	G353D	0.999
9:136418624:G:A	G354R	0.999
9:136418624:G:C	G354R	0.999
9:136418625:G:A	G354E	0.999
9:136418627:C:T	P355S	0.999

dbSNP variants (sampled 300 via entrez): RS1000280431 (9:136412300 C>A,T), RS1000479449 (9:136412286 A>G), RS1000642106 (9:136413607 T>G), RS1000657084 (9:136421331 G>A), RS1000692946 (9:136418428 T>G), RS1000840705 (9:136408835 G>A), RS1000927397 (9:136416057 G>A,C), RS1001131871 (9:136411208 C>G,T), RS1001196905 (9:136413066 C>T), RS1001253464 (9:136416311 C>G,T), RS1001356846 (9:136408977 A>G), RS1001669132 (9:136412724 A>G), RS1001869737 (9:136421411 T>G), RS1001994963 (9:136421629 G>A,T), RS1002282720 (9:136421567 G>A)

Disease associations

OMIM: gene MIM:613036 | disease phenotypes: MIM:213300, MIM:610156, MIM:213200, MIM:236690, MIM:119800, MIM:607411, MIM:204000

GenCC curated gene-disease

Disease	Classification	Inheritance
Joubert syndrome 1	Definitive	Autosomal recessive
MORM syndrome	Definitive	Autosomal recessive
autosomal recessive spinocerebellar ataxia 2	Strong	Autosomal recessive
COACH syndrome 1	Supportive	Autosomal recessive
Joubert syndrome with ocular defect	Supportive	Autosomal recessive
Joubert syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (3)

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

Disease	Classification	Inheritance
mitochondrial disease	Definitive	AR
MORM syndrome	Moderate	AR
Joubert syndrome 1	Definitive	AR

Mondo (22): Joubert syndrome 1 (MONDO:0008944), MORM syndrome (MONDO:0012423), Joubert syndrome (MONDO:0018772), autosomal recessive spinocerebellar ataxia 2 (MONDO:0008943), inherited retinal dystrophy (MONDO:0019118), cerebellar ataxia (MONDO:0000437), Joubert syndrome and related disorders (MONDO:0015369), blindness (disorder) (MONDO:0001941), optic atrophy (MONDO:0003608), hypertrophic cardiomyopathy (MONDO:0005045), normal pressure hydrocephalus (MONDO:0009366), clubfoot (MONDO:0007342), patent ductus arteriosus (MONDO:0011827), interstitial lung disease (MONDO:0015925), femoral agenesis/hypoplasia (MONDO:0016032)

Orphanet (16): Isolated Joubert syndrome (Orphanet:475), MORM syndrome (Orphanet:75858), Autosomal recessive cerebelloparenchymal disorder type 3 (Orphanet:1170), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Rare ataxia (Orphanet:102002), Joubert syndrome and related disorders (Orphanet:140874), Rare hypertrophic cardiomyopathy (Orphanet:217569), Interstitial lung disease (Orphanet:182095), Isolated femoral agenesis/hypoplasia (Orphanet:1987), Familial clubfoot with or without associated lower limb anomalies (Orphanet:199315), Cleft palate (Orphanet:2014), Primary bone dysplasia (Orphanet:364526), Leber congenital amaurosis (Orphanet:65), NON RARE IN EUROPE: Normal pressure hydrocephalus (Orphanet:314928), Familial patent arterial duct (Orphanet:466729)

HPO phenotypes

147 total (30 of 147 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000054	Micropenis
HP:0000077	Abnormality of the kidney
HP:0000083	Renal insufficiency
HP:0000107	Renal cyst
HP:0000112	Nephropathy
HP:0000158	Macroglossia
HP:0000175	Cleft palate
HP:0000202	Orofacial cleft
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000276	Long face
HP:0000286	Epicanthus
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000426	Prominent nasal bridge
HP:0000463	Anteverted nares
HP:0000480	Retinal coloboma
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000543	Optic disc pallor
HP:0000556	Retinal dystrophy
HP:0000567	Chorioretinal coloboma
HP:0000570	Abnormal saccadic eye movements
HP:0000572	Visual loss

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST000964_39	Ulcerative colitis	3.000000e-19
GCST001725_102	Inflammatory bowel disease	4.000000e-56
GCST004131_21	Inflammatory bowel disease	5.000000e-36
GCST004132_11	Crohn’s disease	6.000000e-30
GCST004133_17	Ulcerative colitis	2.000000e-16
GCST004609_10	Monocyte percentage of white cells	7.000000e-11
GCST004610_106	White blood cell count	9.000000e-16
GCST004613_129	Sum neutrophil eosinophil counts	3.000000e-17
GCST004614_34	Granulocyte count	3.000000e-17
GCST004620_28	Sum basophil neutrophil counts	6.000000e-16
GCST004626_75	Myeloid white cell count	5.000000e-16
GCST004629_86	Neutrophil count	6.000000e-16
GCST005989_20	Serum total protein levels	2.000000e-08
GCST006001_25	Hemoglobin A1c levels	8.000000e-11
GCST007576_136	Chronotype	8.000000e-10
GCST008643_2	Joint damage in rheumatoid arthritis	1.000000e-06
GCST010243_2	Apolipoprotein B levels	2.000000e-14
GCST010245_63	LDL cholesterol levels	1.000000e-11
GCST90002398_167	Neutrophil count	8.000000e-41
GCST90002404_481	Red cell distribution width	3.000000e-13
GCST90002407_83	White blood cell count	8.000000e-35
GCST90013406_135	Liver enzyme levels (alkaline phosphatase)	3.000000e-28
GCST90020028_35	Hip circumference adjusted for BMI	5.000000e-13
GCST90020028_36	Hip circumference adjusted for BMI	4.000000e-14

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0007989	monocyte percentage of leukocytes
EFO:0004833	neutrophil count
EFO:0004842	eosinophil count
EFO:0007987	granulocyte count
EFO:0005090	basophil count
EFO:0004541	HbA1c measurement
EFO:0008328	chronotype measurement
EFO:0005413	joint damage measurement
EFO:0004615	apolipoprotein B measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0009188	Red cell distribution width
EFO:0004533	alkaline phosphatase measurement
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (15)

Descriptor	Name	Tree numbers
D001766	Blindness	C10.597.751.941.162; C11.966.075; C23.888.592.763.941.162
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D002972	Cleft Palate	C05.500.460.185; C05.660.207.540.460.185; C07.320.440.185; C07.465.525.185; C07.650.500.460.185; C07.650.525.185; C16.131.621.207.540.460.185; C16.131.850.500.460.185; C16.131.850.525.185
D003025	Clubfoot	C05.330.488.655.063; C05.330.495.681.063; C05.660.585.512.380.813.063; C16.131.621.585.512.500.681.063
D004374	Ductus Arteriosus, Patent	C14.240.400.340; C14.280.400.340; C16.131.240.400.340
D005923	Glomerulosclerosis, Focal Segmental	C12.050.351.968.419.570.363.640; C12.200.777.419.570.363.660; C12.950.419.570.363.640
D006850	Hydrocephalus, Normal Pressure	C10.228.140.602.750
D057130	Leber Congenital Amaurosis	C11.270.516; C11.768.364
D017563	Lung Diseases, Interstitial	C08.381.483
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D012131	Respiratory Insufficiency	C08.618.846
D058499	Retinal Dystrophies	C11.768.585.658
C536984	MORM syndrome (supp.)
C565865	Spinocerebellar Ataxia, Autosomal Recessive 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295809 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, affects expression, decreases expression	3
bisphenol F	increases expression, affects cotreatment, decreases expression	2
bisphenol A	increases expression, decreases methylation	2
bisphenol S	increases expression, increases methylation	2
Cisplatin	affects cotreatment, increases expression, decreases expression	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases expression, decreases reaction	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
CGP 52608	increases reaction, affects binding	1
bisphenol B	increases expression	1
jinfukang	affects cotreatment, increases expression	1
bisphenol AF	increases 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	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Acetaminophen	affects expression	1
Benztropine	increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Dexamethasone	decreases expression, affects cotreatment	1
Doxorubicin	decreases expression	1
Endosulfan	increases expression	1
Formaldehyde	decreases expression	1
Haloperidol	increases expression	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
CHEMBL4232647	Binding	Binding affinity to PMPCA cysteine residue in human 786-O cell soluble proteomic lysate at 5 uM incubated for 1 hr followed by cell lysis by IA-alkyne probe based isoTOP-ABPP analysis	Covalent inhibitors of nicotinamide N-methyltransferase (NNMT) provide evidence for target engagement challenges in situ. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT04107740	PHASE4	COMPLETED	C-Trelin Orally Disintegrated(OD) Tablet 5mg in Ataxia Due to Spinocerebellar Degeneration
NCT00879060	PHASE4	COMPLETED	Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
NCT01721967	PHASE4	COMPLETED	Ranolazine for the Treatment of Chest Pain in HCM Patients
NCT02948998	PHASE4	UNKNOWN	Evaluating the Effect of Spironolactone on Hypertrophic Cardiomyopathy
NCT03249272	PHASE4	TERMINATED	Microvascular Dysfunction in Nonischemic Cardiomyopathy: Insights From CMR Assessment of Coronary Flow Reserve
NCT04133532	PHASE4	COMPLETED	Effect of Metoprolol in Post Alcohol Septal Ablation Patients With Hypertrophic Cardiomyopathy
NCT06401343	PHASE4	RECRUITING	Use of SGLT2i in noHCM With HFpEF
NCT07103655	PHASE4	NOT_YET_RECRUITING	The Therapeutic Value of Mavacamten in Hypertrophic Cardiomyopathy With Mid-to-Apical Left Ventricular Obstruction
NCT07600177	PHASE4	RECRUITING	Mavacamten to Aficamten Transition in Patients With Obstructive Hypertrophic Cardiomyopathy
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
NCT01970098	PHASE3	COMPLETED	A Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970111	PHASE3	COMPLETED	An Extension Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970124	PHASE3	COMPLETED	A Long-Term Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT01970137	PHASE3	COMPLETED	A 24-week Open-label Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT02889302	PHASE3	COMPLETED	An Additional Confirmatory Study of KPS-0373 in Patients With Spinocerebellar Degeneration (SCD)
NCT03408080	PHASE3	ACTIVE_NOT_RECRUITING	Open Pilot Trial of BHV-4157
NCT03701399	PHASE3	ACTIVE_NOT_RECRUITING	Troriluzole in Adult Participants With Spinocerebellar Ataxia
NCT03901638	PHASE3	TERMINATED	Tllsh2910 for Ataxia and Gut Microbiota Alteration in Patients of Multiple System Atrophy
NCT07040137	PHASE3	RECRUITING	Confirmatory Study 3 of KPS-0373 in Patients With Spinocerebellar Degeneration
NCT00317967	PHASE3	COMPLETED	Study to Determine if Atorvastatin Reduces Size and Stiffness of Muscle in the Left Ventricle of the Heart
NCT00698074	PHASE3	UNKNOWN	Diastolic Ventricular Interaction and the Effects of Biventricular Pacing in Hypertrophic Cardiomyopathy
NCT00821353	PHASE3	COMPLETED	Antiarrhythmic Therapy Versus Catheter Ablation for Atrial Fibrillation in Hypertrophic Cardiomyopathy
NCT02431221	PHASE3	WITHDRAWN	Efficacy, Safety, and Tolerability of Perhexiline in Subjects With Hypertrophic Cardiomyopathy and Heart Failure
NCT03470545	PHASE3	COMPLETED	Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT05174416	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mavacamten in Chinese Adults With Symptomatic Obstructive HCM
NCT05182658	PHASE3	ACTIVE_NOT_RECRUITING	Empagliflozin in Hypertrophic Cardiomyopathy
NCT05186818	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM
NCT05767346	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM
NCT06116968	PHASE3	COMPLETED	An Open-Label Study of Aficamten for Chinese Patients With Symptomatic oHCM
NCT06873828	PHASE3	NOT_YET_RECRUITING	Evaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter MonitoringEvaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter Monitoring
NCT07021976	PHASE3	RECRUITING	A Phase III Trial of HRS-1893 in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT07023341	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Learn More About How Well Aficamten Works in Japanese Participants With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT07202897	PHASE3	NOT_YET_RECRUITING	LA-HCM Study : Rivaroxaban for Antithrombotic Prevention in Hypertrophic Cardiomyopathy Patients With Abnormal Left Atrial Strain.
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]
NCT00034242	PHASE2	COMPLETED	High-Dose Intravenous Immunoglobulin to Treat Cerebellar Degeneration
NCT00202397	PHASE2	COMPLETED	Effect of Riluzole as a Symptomatic Approach in Patients With Chronic Cerebellar Ataxia