PMPCB

Summary

PMPCB (peptidase, mitochondrial processing subunit beta, HGNC:9119) is a protein-coding gene on chromosome 7q22.1, encoding Mitochondrial-processing peptidase subunit beta (O75439). Catalytic subunit of the essential mitochondrial processing protease (MPP), which cleaves the mitochondrial sequence off newly imported precursors proteins.

This gene is a member of the peptidase M16 family and encodes a protein with a zinc-binding motif. This protein is located in the mitochondrial matrix and catalyzes the cleavage of the leader peptides of precursor proteins newly imported into the mitochondria, though it only functions as part of a heterodimeric complex.

Source: NCBI Gene 9512 — RefSeq curated summary.

At a glance

• Gene–disease (curated): multiple mitochondrial dysfunctions syndrome 6 (Strong, GenCC)
• GWAS associations: 7
• Clinical variants (ClinVar): 235 total — 3 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 27
• Druggable target: yes
• MANE Select transcript: NM_004279

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9119
Approved symbol	PMPCB
Name	peptidase, mitochondrial processing subunit beta
Location	7q22.1
Locus type	gene with protein product
Status	Approved
Aliases	MPPB, MPPP52, MAS1, beta-MPP
Ensembl gene	ENSG00000105819
Ensembl biotype	protein_coding
OMIM	603131
Entrez	9512

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 15 protein_coding, 15 nonsense_mediated_decay, 9 retained_intron

ENST00000249269, ENST00000428154, ENST00000443722, ENST00000444457, ENST00000453466, ENST00000456433, ENST00000469560, ENST00000498530, ENST00000706437, ENST00000706438, ENST00000706439, ENST00000706440, ENST00000706441, ENST00000706442, ENST00000706443, ENST00000706447, ENST00000706448, ENST00000706449, ENST00000706450, ENST00000706451, ENST00000706452, ENST00000706453, ENST00000706454, ENST00000706455, ENST00000706456, ENST00000706457, ENST00000706458, ENST00000706459, ENST00000706460, ENST00000706461, ENST00000706462, ENST00000706463, ENST00000900040, ENST00000900041, ENST00000900042, ENST00000900043, ENST00000900044, ENST00000915585, ENST00000943376

RefSeq mRNA: 1 — MANE Select: NM_004279 NM_004279

CCDS: CCDS5730

Canonical transcript exons

ENST00000249269 — 13 exons

Exon	Start	End
ENSE00001238318	103312207	103314686
ENSE00001712196	103297435	103297558
ENSE00003459477	103298568	103298708
ENSE00003474057	103300178	103300307
ENSE00003513090	103304411	103304490
ENSE00003548631	103311643	103311728
ENSE00003555727	103303842	103304040
ENSE00003575602	103308952	103309095
ENSE00003621551	103299443	103299529
ENSE00003622916	103312056	103312131
ENSE00003647943	103310315	103310475
ENSE00003661060	103307596	103307708
ENSE00003672017	103311808	103311896

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 97.14.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 94.1263 / max 943.4404, expressed in 1825 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
80276	93.7993	1825
80277	0.2844	38
80278	0.0426	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland cortex	UBERON:0035827	97.14	gold quality
right adrenal gland	UBERON:0001233	97.03	gold quality
adrenal tissue	UBERON:0018303	96.99	gold quality
parotid gland	UBERON:0001831	96.92	gold quality
left adrenal gland	UBERON:0001234	96.79	gold quality
body of pancreas	UBERON:0001150	96.76	gold quality
adrenal cortex	UBERON:0001235	96.65	gold quality
left adrenal gland cortex	UBERON:0035825	96.63	gold quality
upper leg skin	UBERON:0004262	96.58	gold quality
mucosa of stomach	UBERON:0001199	96.41	gold quality
rectum	UBERON:0001052	96.40	gold quality
skin of hip	UBERON:0001554	96.40	gold quality
adrenal gland	UBERON:0002369	96.38	gold quality
left ovary	UBERON:0002119	95.99	gold quality
metanephros cortex	UBERON:0010533	95.93	gold quality
tibial artery	UBERON:0007610	95.92	gold quality
popliteal artery	UBERON:0002250	95.91	gold quality
heart right ventricle	UBERON:0002080	95.76	gold quality
parietal pleura	UBERON:0002400	95.75	gold quality
artery	UBERON:0001637	95.74	gold quality
body of stomach	UBERON:0001161	95.73	gold quality
body of uterus	UBERON:0009853	95.66	gold quality
descending thoracic aorta	UBERON:0002345	95.65	gold quality
transverse colon	UBERON:0001157	95.62	gold quality
gall bladder	UBERON:0002110	95.61	gold quality
right atrium auricular region	UBERON:0006631	95.60	gold quality
ovary	UBERON:0000992	95.57	gold quality
aorta	UBERON:0000947	95.51	gold quality
duodenum	UBERON:0002114	95.51	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.48	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTCF

miRNA regulators (miRDB)

130 targeting PMPCB, 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-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-605-3P	99.88	69.22	1833

Literature-anchored findings (GeneRIF, showing 5)

• maintained expression and even up-regulation of some (PNPT1, PMPCB, HMMR/RHAMM, BSG and ERCC1) tumor associated antigens in CD40-activated leukemic cells. (PMID:19580345)
• These results highlight a new role for MPP in PINK1 import and mitochondrial quality control via the PINK1-Parkin pathway. (PMID:22354088)
• OxLDL triggers retrograde translocation of arginase2 in aortic endothelial cells via ROCK and mitochondrial processing peptidase. (PMID:24903103)
• biallelic mutations in PMPCB cause defects in MPP proteolytic activity leading to dysregulation of iron-sulfur cluster biogenesis and triggering a complex neurological phenotype of neurodegeneration in early childhood. (PMID:29576218)
• Silencing PMPCB increased hepatocellular carcinoma (HCC) susceptibility to sorafenib, decreased tumor burden, and improved survival. These results suggest contributory role of the PMPCB in sorafenib resistance. (PMID:31337603)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pmpcb	ENSDARG00000016979
mus_musculus	Pmpcb	ENSMUSG00000029017
rattus_norvegicus	Pmpcb	ENSRNOG00000012693
drosophila_melanogaster	UQCR-C1	FBGN0038271
caenorhabditis_elegans		WBGENE00013880

Paralogs (6): UQCRC1 (ENSG00000010256), NRDC (ENSG00000078618), PITRM1 (ENSG00000107959), IDE (ENSG00000119912), UQCRC2 (ENSG00000140740), PMPCA (ENSG00000165688)

Protein

Protein identifiers

Mitochondrial-processing peptidase subunit beta — O75439 (reviewed: O75439)

Alternative names: Beta-MPP, P-52

All UniProt accessions (17): O75439, A0A9L9PWW3, A0A9L9PWX2, A0A9L9PX42, A0A9L9PX50, A0A9L9PX59, A0A9L9PXG6, A0A9L9PXH0, A0A9L9PXH4, A0A9L9PXH7, A0A9L9PXI7, A0A9L9PY03, F8WAZ6, F8WBE1, F8WEA6, F8WEC8, G3V0E4

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of the essential mitochondrial processing protease (MPP), which cleaves the mitochondrial sequence off newly imported precursors proteins. Preferentially, cleaves after an arginine at position P2. Required for PINK1 turnover by coupling PINK1 mitochondrial import and cleavage, which results in subsequent PINK1 proteolysis.

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.

Disease relevance. Multiple mitochondrial dysfunctions syndrome 6 (MMDS6) [MIM:617954] An autosomal recessive, neurodegenerative disorder characterized by basal ganglia lesions, cerebellar atrophy, and neurologic regression in the first year of life. Common features include truncal hypotonia, lack of independent ambulation, poor speech, intellectual disability, and motor abnormalities, such as ataxia, dystonia, and spasticity. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Binding to PMPCA is required for catalytic activity.

Cofactor. Binds 1 zinc ion per subunit.

Similarity. Belongs to the peptidase M16 family.

RefSeq proteins (1): NP_004270* (*=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 (15 total): sequence variant 6, binding site 3, site 2, transit peptide 1, chain 1, sequence conflict 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75439-F1	87.48	0.79

Functional residue map

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

Catalytic / active sites (3): 104 (proton acceptor); 191 (required for the specific determination of the substrate cleavage site); 195 (required for the specific determination of the substrate cleavage site)

Ligand- & substrate-binding residues (3): 101; 105; 181

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

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

MSigDB gene sets: 301 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_INFLAMMATORY_RESPONSE, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_RESPONSE_TO_ANGIOTENSIN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_PROTEIN_TARGETING, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE, TATTATA_MIR374, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND

GO Biological Process (4): obsolete protein processing involved in protein targeting to mitochondrion (GO:0006627), mitochondrial calcium ion transmembrane transport (GO:0006851), protein processing (GO:0016485), proteolysis (GO:0006508)

GO Molecular Function (6): metalloendopeptidase activity (GO:0004222), signal peptidase activity (GO:0009003), metal ion binding (GO:0046872), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787)

GO Cellular Component (3): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), mitochondrial processing peptidase complex (GO:0017087)

Reactome top-level categories

Rollup of top-3 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endopeptidase activity	2
calcium ion transmembrane transport	1
proteolysis	1
protein maturation	1
protein metabolic process	1
metallopeptidase activity	1
cation binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
mitochondrial matrix	1
mitochondrial protein-containing complex	1
endopeptidase complex	1

Protein interactions and networks

STRING

3649 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PMPCB	PMPCA	Q10713	947
PMPCB	FXN	Q16595	765
PMPCB	MIPEP	Q99797	646
PMPCB	XPNPEP3	Q9NQH7	643
PMPCB	TOMM40	O96008	635
PMPCB	AFG3L2	Q9Y4W6	559
PMPCB	LONP1	P36776	541
PMPCB	TIMM17A	Q99595	540
PMPCB	CLPP	Q16740	527
PMPCB	IMMP1L	Q96LU5	508
PMPCB	YME1L1	Q96TA2	507
PMPCB	METAP1D	Q6UB28	505
PMPCB	IMMP2L	Q96T52	492
PMPCB	MRPL15	Q9P015	480
PMPCB	HSPA9	P30036	470

IntAct

163 interactions, top by confidence:

A	B	Type	Score
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
	PMPCB	psi-mi:“MI:0914”(association)	0.640
MRPS30	GTPBP10	psi-mi:“MI:0914”(association)	0.640
ODAPH	TCAF2	psi-mi:“MI:0914”(association)	0.530
NPPA	A2ML1	psi-mi:“MI:0914”(association)	0.530
SOST	KPNA4	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
PMPCB	AMY1A	psi-mi:“MI:0914”(association)	0.530
	PMPCB	psi-mi:“MI:0914”(association)	0.530
PMPCA	PMPCB	psi-mi:“MI:0914”(association)	0.530
PMPCB	PPP4R3A	psi-mi:“MI:0914”(association)	0.530
MMAB	PMPCB	psi-mi:“MI:0914”(association)	0.530
NPPA	VGF	psi-mi:“MI:0914”(association)	0.530
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
SLC11A2	PMPCB	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (454): PMPCB (Affinity Capture-RNA), PMPCB (Affinity Capture-RNA), PMPCB (Affinity Capture-RNA), PMPCB (Affinity Capture-RNA), PMPCB (Affinity Capture-MS), SMEK1 (Affinity Capture-MS), SMEK2 (Affinity Capture-MS), PPP4R1 (Affinity Capture-MS), AMY1C (Affinity Capture-MS), PMPCB (Affinity Capture-MS), PMPCB (Affinity Capture-MS), PMPCB (Co-fractionation), PNPT1 (Co-fractionation), PRDX5 (Co-fractionation), PMPCB (Proximity Label-MS)

ESM2 similar proteins: A0A1F3, A3KP37, O75439, P00337, P00339, P04642, P06151, P11913, P13491, P13743, P19858, P20069, P28492, P31800, P31930, P79912, P79913, Q00302, Q03346, Q0P5M8, Q10713, Q23295, Q3SZ71, Q42290, Q571F8, Q5R1W9, Q5R513, Q5R5F0, Q5RBS1, Q5REK3, Q68FY0, Q6DGK2, Q8VY06, Q98SK9, Q98SL0, Q9BE24, Q9CXT8, Q9CZ13, Q9DC61, Q9LJL3

Diamond homologs: B8B0E2, F4HNU6, O14077, O75439, P11913, P31800, P31828, P31930, P45181, Q03346, Q3SZ71, Q40983, Q5REK3, Q68FY0, Q69TY5, Q8Z418, Q8ZMB5, Q9CXT8, Q9CZ13, Q9FIH8, O05945, O31766, O32965, O86835, P0A5S9, P10507, P9WHT4, P9WHT5, Q00302, Q04805, Q1RJ61, Q42290, Q4UML9, Q4W6B5, Q68XF0, Q92IX7, Q9P7X1, Q9Y8B5, P05458, P29677

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PMPCB	“down-regulates quantity by destabilization”	PINK1	cleavage

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 136 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
Complex I biogenesis	6	10.8×	2e-03
Mitochondrial protein degradation	8	9.9×	3e-04
Aerobic respiration and respiratory electron transport	8	7.7×	1e-03
Respiratory electron transport	7	7.2×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
ubiquinone biosynthetic process	6	46.0×	2e-06
mitochondrial electron transport, NADH to ubiquinone	7	20.6×	2e-05
proton motive force-driven mitochondrial ATP synthesis	7	15.1×	1e-04
aerobic respiration	6	12.2×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	5
Uncertain significance	147
Likely benign	45
Benign	17

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
523140	NM_004279.3(PMPCB):c.524G>A (p.Arg175His)	Pathogenic
523141	NM_004279.3(PMPCB):c.530T>G (p.Val177Gly)	Pathogenic
523142	NM_004279.3(PMPCB):c.1265T>C (p.Ile422Thr)	Pathogenic
1342344	NM_004279.3(PMPCB):c.606T>A (p.Tyr202Ter)	Likely pathogenic
2500914	NM_004279.3(PMPCB):c.543_544del (p.Glu181fs)	Likely pathogenic
2580358	NM_004279.3(PMPCB):c.1154+5G>C	Likely pathogenic
2585259	NM_004279.3(PMPCB):c.1078dup (p.Thr360fs)	Likely pathogenic
523138	NM_004279.3(PMPCB):c.523C>T (p.Arg175Cys)	Likely pathogenic

SpliceAI

3592 predictions. Top by Δscore:

Variant	Effect	Δscore
7:103298549:A:AG	acceptor_gain	1.0000
7:103298550:C:G	acceptor_gain	1.0000
7:103298704:GCACA:G	donor_gain	1.0000
7:103298709:G:GG	donor_gain	1.0000
7:103299430:T:TA	acceptor_gain	1.0000
7:103299434:T:A	acceptor_gain	1.0000
7:103299437:A:AG	acceptor_gain	1.0000
7:103299438:T:G	acceptor_gain	1.0000
7:103299438:TTAA:T	acceptor_loss	1.0000
7:103299439:TAA:T	acceptor_loss	1.0000
7:103299440:AAGGT:A	acceptor_loss	1.0000
7:103299441:A:G	acceptor_gain	1.0000
7:103299442:G:T	acceptor_loss	1.0000
7:103299534:GTT:G	donor_gain	1.0000
7:103299537:G:GG	donor_gain	1.0000
7:103300173:TCAAG:T	acceptor_loss	1.0000
7:103300174:CAA:C	acceptor_loss	1.0000
7:103300175:A:AG	acceptor_gain	1.0000
7:103300175:AAG:A	acceptor_gain	1.0000
7:103300175:AAGG:A	acceptor_gain	1.0000
7:103300176:A:G	acceptor_gain	1.0000
7:103300176:AG:A	acceptor_gain	1.0000
7:103300177:G:A	acceptor_gain	1.0000
7:103300177:G:GG	acceptor_gain	1.0000
7:103300303:AAGAG:A	donor_loss	1.0000
7:103300305:G:GT	donor_gain	1.0000
7:103300305:GAG:G	donor_gain	1.0000
7:103300305:GAGG:G	donor_loss	1.0000
7:103300307:GGTAC:G	donor_loss	1.0000
7:103300308:G:C	donor_loss	1.0000

AlphaMissense

3188 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:103299444:T:A	V81D	1.000
7:103299446:G:A	G82R	1.000
7:103299446:G:C	G82R	1.000
7:103299447:G:A	G82E	1.000
7:103299452:T:A	W84R	1.000
7:103299452:T:C	W84R	1.000
7:103299464:G:A	G88R	1.000
7:103299464:G:C	G88R	1.000
7:103299465:G:A	G88E	1.000
7:103299465:G:T	G88V	1.000
7:103299467:A:C	S89R	1.000
7:103299469:T:A	S89R	1.000
7:103299469:T:G	S89R	1.000
7:103299495:G:A	G98E	1.000
7:103299495:G:T	G98V	1.000
7:103299503:C:G	H101D	1.000
7:103299505:C:A	H101Q	1.000
7:103299505:C:G	H101Q	1.000
7:103299510:T:C	L103P	1.000
7:103299513:A:T	E104V	1.000
7:103299514:G:C	E104D	1.000
7:103299514:G:T	E104D	1.000
7:103299515:C:A	H105N	1.000
7:103299515:C:G	H105D	1.000
7:103299516:A:C	H105P	1.000
7:103299516:A:T	H105L	1.000
7:103299517:T:A	H105Q	1.000
7:103299517:T:G	H105Q	1.000
7:103299524:T:A	F108I	1.000
7:103299524:T:C	F108L	1.000

dbSNP variants (sampled 300 via entrez): RS1000003336 (7:103344183 G>A,C), RS1000022831 (7:103296501 C>A,G), RS1000267442 (7:103320966 G>C), RS1000273187 (7:103332394 C>T), RS1000442108 (7:103315041 G>A), RS1000465639 (7:103337974 A>C), RS1000498409 (7:103336705 T>C), RS1000514424 (7:103339131 G>A), RS1000638608 (7:103331445 A>G), RS1000732248 (7:103301728 A>G), RS1000784337 (7:103321271 C>T), RS1000907253 (7:103343742 G>A), RS1000916135 (7:103298013 G>A), RS1000975790 (7:103303801 A>G), RS1001033487 (7:103312444 G>A)

Disease associations

OMIM: gene MIM:603131 | disease phenotypes: MIM:617954, MIM:257320, MIM:616436

GenCC curated gene-disease

Disease	Classification	Inheritance
multiple mitochondrial dysfunctions syndrome 6	Strong	Autosomal recessive

Mondo (3): multiple mitochondrial dysfunctions syndrome 6 (MONDO:0054785), Norman-Roberts syndrome (MONDO:0009760), familial temporal lobe epilepsy 7 (MONDO:0014639)

Orphanet (3): Multiple mitochondrial dysfunctions syndrome type 6 (Orphanet:569290), Epilepsy with auditory features (Orphanet:101046), Lissencephaly syndrome, Norman-Roberts type (Orphanet:89844)

HPO phenotypes

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

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000572	Visual loss
HP:0000648	Optic atrophy
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001310	Dysmetria
HP:0001332	Dystonia
HP:0001344	Absent speech
HP:0001508	Failure to thrive
HP:0002151	Increased circulating lactate concentration
HP:0002352	Leukoencephalopathy
HP:0002376	Developmental regression
HP:0002421	Poor head control
HP:0002540	Inability to walk
HP:0003593	Infantile onset
HP:0003676	Progressive
HP:0005484	Secondary microcephaly
HP:0007366	Atrophy/Degeneration affecting the brainstem
HP:0011463	Childhood onset
HP:0011968	Feeding difficulties
HP:0200134	Epileptic encephalopathy

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST003127_12	Lipoprotein (a) levels	5.000000e-11
GCST005950_13	Body mass index x sex x age interaction (4df test)	3.000000e-07
GCST005951_54	Body mass index	4.000000e-06
GCST005952_6	Body mass index (age>50)	2.000000e-08
GCST006479_111	Diverticular disease	4.000000e-14
GCST009391_439	Metabolite levels	8.000000e-06
GCST012490_51	Femur bone mineral density x serum urate levels interaction	2.000000e-11

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0006925	lipoprotein A measurement
EFO:0004340	body mass index
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0009959	diverticular disease
EFO:0010385	phosphatidylcholine 38:3 measurement
EFO:0004531	urate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067010 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.32	Kd	47.61	nM	CHEMBL5653589
7.32	ED50	47.61	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 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-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149028: Binding affinity to human PMPCB incubated for 45 mins by Kinobead based pull down assay	kd	0.0476	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
arsenite	decreases methylation	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
microcystin RR	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	increases reaction, affects binding	1
corosolic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
MT19c compound	increases expression	1
bisphenol AF	increases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Atrazine	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	decreases phosphorylation	1
Coumestrol	decreases expression, affects cotreatment	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ivermectin	decreases expression	1
Ozone	affects expression, increases abundance	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
CHEMBL5652070	Binding	Binding affinity to human PMPCB 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)

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