PRORP

Summary

PRORP (protein only RNase P catalytic subunit, HGNC:19958) is a protein-coding gene on chromosome 14q13.2, encoding Mitochondrial ribonuclease P catalytic subunit (O15091). Catalytic ribonuclease component of mitochondrial ribonuclease P, a complex composed of TRMT10C/MRPP1, HSD17B10/MRPP2 and PRORP/MRPP3, which cleaves tRNA molecules in their 5’-ends. It is a selective cancer dependency (DepMap: 42.9% of cell lines).

Enables ribonuclease P activity. Involved in mitochondrial tRNA 5’-end processing. Located in mitochondrion and nucleoplasm. Part of mitochondrial ribonuclease P complex. Implicated in combined oxidative phosphorylation deficiency 54.

Source: NCBI Gene 9692 — RefSeq curated summary.

At a glance

• Gene–disease (curated): mitochondrial disease (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 10
• Clinical variants (ClinVar): 99 total — 2 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 45
• Cancer dependency (DepMap): dependent in 42.9% of screened cell lines
• MANE Select transcript: NM_014672

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19958
Approved symbol	PRORP
Name	protein only RNase P catalytic subunit
Location	14q13.2
Locus type	gene with protein product
Status	Approved
Aliases	MRPP3
Ensembl gene	ENSG00000100890
Ensembl biotype	protein_coding
OMIM	609947
Entrez	9692

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 18 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000250377, ENST00000321130, ENST00000534898, ENST00000557404, ENST00000603544, ENST00000603588, ENST00000603611, ENST00000604073, ENST00000604948, ENST00000605201, ENST00000605870, ENST00000887494, ENST00000887495, ENST00000887496, ENST00000887497, ENST00000887498, ENST00000887499, ENST00000928184, ENST00000947894

RefSeq mRNA: 6 — MANE Select: NM_014672 NM_001256678, NM_001256679, NM_001256680, NM_001256681, NM_001414503, NM_014672

CCDS: CCDS32063, CCDS58312, CCDS58313, CCDS58314

Canonical transcript exons

ENST00000534898 — 8 exons

Exon	Start	End
ENSE00002294502	35122552	35122635
ENSE00003458377	35127479	35127611
ENSE00003485950	35270401	35270596
ENSE00003525153	35122952	35124231
ENSE00003563542	35273435	35277622
ENSE00003602764	35126735	35126782
ENSE00003634374	35266727	35266875
ENSE00003644029	35180670	35180777

Expression profiles

Bgee: expression breadth ubiquitous, 177 present calls, max score 88.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.9161 / max 314.8881, expressed in 1818 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
139212	23.3504	1806
139213	6.3499	1656
139214	2.0911	937
139208	0.8511	593
139211	0.7554	396
139210	0.6499	375
139215	0.5420	255
139209	0.3263	126

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.82	gold quality
rectum	UBERON:0001052	88.47	gold quality
mucosa of transverse colon	UBERON:0004991	87.85	gold quality
stromal cell of endometrium	CL:0002255	86.31	gold quality
right adrenal gland	UBERON:0001233	85.41	gold quality
adrenal tissue	UBERON:0018303	85.37	gold quality
ventricular zone	UBERON:0003053	85.21	gold quality
right adrenal gland cortex	UBERON:0035827	85.07	gold quality
islet of Langerhans	UBERON:0000006	84.99	gold quality
left adrenal gland	UBERON:0001234	84.81	gold quality
calcaneal tendon	UBERON:0003701	84.79	gold quality
left adrenal gland cortex	UBERON:0035825	84.50	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.15	gold quality
skin of abdomen	UBERON:0001416	83.98	gold quality
cortical plate	UBERON:0005343	83.83	gold quality
skin of leg	UBERON:0001511	83.79	gold quality
ganglionic eminence	UBERON:0004023	83.50	gold quality
granulocyte	CL:0000094	83.13	gold quality
esophagus mucosa	UBERON:0002469	83.00	gold quality
leukocyte	CL:0000738	82.92	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	82.92	gold quality
adrenal gland	UBERON:0002369	82.85	gold quality
gastrocnemius	UBERON:0001388	82.83	gold quality
monocyte	CL:0000576	82.73	gold quality
upper lobe of left lung	UBERON:0008952	82.66	gold quality
muscle of leg	UBERON:0001383	82.64	gold quality
right lobe of liver	UBERON:0001114	82.56	gold quality
mononuclear cell	CL:0000842	82.43	gold quality
descending thoracic aorta	UBERON:0002345	82.05	gold quality
gall bladder	UBERON:0002110	82.02	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.37

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

37 targeting PRORP, 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-548C-3P	99.99	74.01	7587
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-510-3P	99.54	70.06	2965
HSA-MIR-12117	99.50	67.57	868
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-4797-5P	99.39	68.01	1354
HSA-MIR-6809-5P	99.13	68.45	1223
HSA-MIR-4695-5P	99.06	64.87	1151
HSA-MIR-1207-3P	98.99	66.22	1532
HSA-MIR-5000-3P	98.79	65.63	1251
HSA-MIR-3945	98.68	64.21	553
HSA-MIR-374C-3P	98.47	67.93	451
HSA-MIR-211-3P	98.14	66.77	1052
HSA-MIR-4518	98.12	66.82	1030
HSA-MIR-18B-3P	98.05	65.55	595
HSA-MIR-1266-5P	97.71	66.92	1052
HSA-MIR-6783-5P	97.67	67.21	1528
HSA-MIR-562	97.66	65.63	698
HSA-MIR-5189-3P	97.52	66.33	487

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 42.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 9)

• Haplotypes in KIAA0391 and PSMA6 genes is a genetic link for myocardial infarction and coronary artery disease. (PMID:19624571)
• Inhibition of mitochondrial RNase P by beta-amyloid is an unspecific effect and is not mediated by beta-amyloid interaction with SDR5C1. (PMID:23755257)
• using a genome-wide association study, found that posttranscriptional modification of functionally important sites in mitochondrial transfer RNAs (tRNAs) is under strong genetic control, largely driven by a missense mutation in MRPP3 (PMID:24763589)
• This study presents the crystal structure of human MRPP3, which features a remarkably distorted and hence non-productive active site that authors propose will switch to a fully productive state only upon association with MRPP1, MRPP2 and pre-tRNA substrate. (PMID:25953853)
• This study proposes low-resolution models of the MRPP1-MRPP2 and MRPP1-MRPP2-MRPP3 complexes that suggest the overall architecture, stoichiometry, and orientation of subunits and tRNA substrates. (PMID:29880640)
• Structural basis of RNA processing by human mitochondrial RNase P. (PMID:34489609)
• Bi-allelic variants in the mitochondrial RNase P subunit PRORP cause mitochondrial tRNA processing defects and pleiotropic multisystem presentations. (PMID:34715011)
• Novel homozygous variants in PRORP expand the genotypic spectrum of combined oxidative phosphorylation deficiency 54. (PMID:37558808)
• Comprehensive functional interrogation of susceptibility loci in GWASs identified KIAA0391 as a novel oncogenic driver via regulating pyroptosis in NSCLC. (PMID:38262497)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	prorp	ENSDARG00000075057
mus_musculus	Prorp	ENSMUSG00000021023
rattus_norvegicus	Prorp	ENSRNOG00000007043
drosophila_melanogaster	mldr	FBGN0029858
caenorhabditis_elegans	coa-6	WBGENE00013893

Protein

Protein identifiers

Mitochondrial ribonuclease P catalytic subunit — O15091 (reviewed: O15091)

Alternative names: Mitochondrial ribonuclease P protein 3, Protein only RNase P catalytic subunit

All UniProt accessions (5): O15091, A0A0A0MTQ0, S4R3S1, S4R3T4, S4R416

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic ribonuclease component of mitochondrial ribonuclease P, a complex composed of TRMT10C/MRPP1, HSD17B10/MRPP2 and PRORP/MRPP3, which cleaves tRNA molecules in their 5’-ends. The presence of TRMT10C/MRPP1, HSD17B10/MRPP2 is required to catalyze tRNA molecules in their 5’-ends.

Subunit / interactions. Catalytic component of mitochondrial ribonuclease P, a complex composed of TRMT10C/MRPP1, HSD17B10/MRPP2 and PRORP/MRPP3.

Subcellular location. Mitochondrion.

Post-translational modifications. Degraded by LONP1 following mitochondrial unfolded protein response, probably leading to inhibit translation in mitochondrion.

Disease relevance. Combined oxidative phosphorylation deficiency 54 (COXPD54) [MIM:619737] An autosomal recessive, multisystem disorder with highly variable manifestations resulting from defective mitochondrial transcription and translation. Clinical features include early-onset sensorineural hearing loss, sometimes associated with global developmental delay or primary ovarian failure, peripheral hypertonia, seizures, muscle weakness, behavioral abnormalities, and leukoencephalopathy on brain imaging. Serum lactate may or may not be elevated. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 2 Mg(2+) or Mg(2+) ions per subunit.

Domain organisation. Displays a distorted and non-productive active site that probably switches to a fully productive state only upon association with TRMT10C/MRPP1, HSD17B10/MRPP2 and pre-tRNA substrate.

Induction. Down-regulated following mitochondrial unfolded protein response.

Similarity. Belongs to the PPR family. P subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
O15091-1	1	yes
O15091-2	2
O15091-3	3
O15091-4	4

RefSeq proteins (6): NP_001243607, NP_001243608, NP_001243609, NP_001243610, NP_001401432, NP_055487* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR031595	PRORP_C	Domain
IPR033495	MRPP3_PIN_dom	Domain

Pfam: PF16953

Enzyme classification (BRENDA):

• EC 3.1.26.5 — ribonuclease P (BRENDA: 188 organisms, 407 substrates, 80 inhibitors, 54 Km, 43 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
HUMAN PRE-TRNATYR	0.0001–0.0005	5
PRE-TRNATYR	—	5
PRE-TRNAASP	—	4
PTRNATYR	0.0002–0.0305	4
TRNA PRECURSOR	—	4
PRE-TRNA-TYR	0.0001	2
PRE-TRNATHR(AGT)	0.0035–0.05	2
RNASE P RIBOSWITCH A	0.0064–0.0081	2
TRNAPHE (G+1) PRECURSOR	—	2
TRNATYR	—	2
PMINI3PBUG	0.0013	1
PRE-TRNA	—	1
PRE-TRNA SUPS1 TRNASER	0.0002	1
PRE-TRNA-ASP	0.0003	1
PRE-TRNA-CYS	0.0006	1

UniProt features (70 total): helix 22, strand 15, binding site 8, mutagenesis site 7, sequence variant 6, splice variant 3, turn 3, sequence conflict 2, transit peptide 1, chain 1, modified residue 1, domain 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
4XGL	X-RAY DIFFRACTION	1.8
4XGM	X-RAY DIFFRACTION	1.98
4ROU	X-RAY DIFFRACTION	2.71
8CBK	ELECTRON MICROSCOPY	2.76
7ONU	ELECTRON MICROSCOPY	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15091-F1	79.19	0.60

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 (8): 578; 348; 351; 409; 478; 479; 499; 557

Post-translational modifications (1): 98

Mutagenesis-validated functional residues (7):

Position	Phenotype
409	abolishes ribonuclease activity.
478	abolishes ribonuclease activity.
479	abolishes ribonuclease activity.
480	does not affect ribonuclease activity.
498	does not affect ribonuclease activity.
499	abolishes ribonuclease activity.
569	does not affect ribonuclease activity.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-6785470	tRNA processing in the mitochondrion
R-HSA-6787450	tRNA modification in the mitochondrion
R-HSA-8868766	rRNA processing in the mitochondrion
R-HSA-72306	tRNA processing
R-HSA-72312	rRNA processing
R-HSA-8953854	Metabolism of RNA

MSigDB gene sets: 241 (showing top): GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, GOMF_NUCLEASE_ACTIVITY, GOBP_TRNA_METABOLIC_PROCESS, BROWNE_HCMV_INFECTION_12HR_UP, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, INAMURA_LUNG_CANCER_SCC_SUBTYPES_UP, GOMF_RNA_ENDONUCLEASE_ACTIVITY, GOBP_MITOCHONDRIAL_RNA_PROCESSING, GOBP_MITOCHONDRIAL_RNA_METABOLIC_PROCESS, MORF_EPHA7, MORF_RAB3A, MORF_WNT1, MORF_IL9, GOBP_TRNA_PROCESSING

GO Biological Process (3): tRNA 5’-leader removal (GO:0001682), mitochondrial tRNA 5’-end processing (GO:0097745), tRNA processing (GO:0008033)

GO Molecular Function (5): ribonuclease P activity (GO:0004526), metal ion binding (GO:0046872), nuclease activity (GO:0004518), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (5): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), mitochondrial ribonuclease P complex (GO:0030678), mitochondrial nucleoid (GO:0042645)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
tRNA processing	2
Metabolism of RNA	2
rRNA processing	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitochondrion	3
tRNA 5’-end processing	2
mitochondrial RNA 5’-end processing	1
mitochondrial tRNA processing	1
RNA processing	1
tRNA metabolic process	1
tRNA-specific ribonuclease activity	1
RNA endonuclease activity producing 5’-phosphomonoesters, hydrolytic mechanism	1
cation binding	1
catalytic activity, acting on a nucleic acid	1
binding	1
catalytic activity	1
nuclear lumen	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
ribonuclease P complex	1
mitochondrial protein-containing complex	1
mitochondrial matrix	1
nucleoid	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1622 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRORP	TRMT10C	Q7L0Y3	998
PRORP	HSD17B10	Q99714	994
PRORP	FSIP1	Q8NA03	805
PRORP	NPAS3	Q8IXF0	766
PRORP	ELAC2	Q9BQ52	722
PRORP	PTCD1	O75127	704
PRORP	PTCD2	Q8WV60	666
PRORP	POP5	Q969H6	648
PRORP	TRMT10A	Q8TBZ6	618
PRORP	PTCD3	Q96EY7	594
PRORP	MRPS27	Q92552	581
PRORP	LRPPRC	P42704	567
PRORP	POLRMT	O00411	552
PRORP	PSMA6	P34062	518
PRORP	PNPT1	Q8TCS8	517

IntAct

111 interactions, top by confidence:

A	B	Type	Score
HSD17B10	PRORP	psi-mi:“MI:0915”(physical association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
HSD17B10		psi-mi:“MI:0915”(physical association)	0.670
HSD17B10		psi-mi:“MI:0902”(rna cleavage)	0.670
BPNT1	GTPBP10	psi-mi:“MI:0914”(association)	0.530
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
IL13RA2	METTL15	psi-mi:“MI:0914”(association)	0.530
UQCRFS1	NDUFAB1	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
PALD1	UNC119B	psi-mi:“MI:0914”(association)	0.530
SLC31A1	PRORP	psi-mi:“MI:0914”(association)	0.530
NTRK3	FAM171A2	psi-mi:“MI:0914”(association)	0.480
HSD17B10		psi-mi:“MI:0902”(rna cleavage)	0.440
Ppp6c	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
COQ9	NDUFS8	psi-mi:“MI:0914”(association)	0.350
ATAD3A	TMEM223	psi-mi:“MI:0914”(association)	0.350
PA	DDX39A	psi-mi:“MI:0914”(association)	0.350
CTDP1	ESYT2	psi-mi:“MI:0914”(association)	0.350
THEM5	PRORP	psi-mi:“MI:0914”(association)	0.350
HIDE1	TMEM120B	psi-mi:“MI:0914”(association)	0.350
S100P	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
GYPA	HYKK	psi-mi:“MI:0914”(association)	0.350
UQCRFS1	VWA8	psi-mi:“MI:0914”(association)	0.350
MALSU1	VWA8	psi-mi:“MI:0914”(association)	0.350

BioGRID (161): KIAA0391 (Affinity Capture-MS), KIAA0391 (Affinity Capture-MS), KIAA0391 (Affinity Capture-MS), KIAA0391 (Affinity Capture-MS), KIAA0391 (Affinity Capture-MS), KIAA0391 (Affinity Capture-MS), KIAA0391 (Affinity Capture-MS), KIAA0391 (Affinity Capture-MS), KIAA0391 (Affinity Capture-MS), KIAA0391 (Affinity Capture-MS), KIAA0391 (Affinity Capture-MS), KIAA0391 (Affinity Capture-MS), KIAA0391 (Affinity Capture-MS), KIAA0391 (Affinity Capture-MS), KIAA0391 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GW35, A6QNM3, B0R034, B1ANS9, B9EK06, D2KC46, D3ZY60, F1MS15, F1P065, F1REV3, O00522, O15091, O75747, P10911, P58069, Q008S8, Q14449, Q14D04, Q15283, Q32NR9, Q45GW3, Q4R366, Q4R6T7, Q5H9U9, Q5K651, Q5PQS3, Q5XGX5, Q5XIZ9, Q5ZLD2, Q60862, Q63713, Q69Z37, Q6DCF6, Q6S5J6, Q6TNJ1, Q75PQ8, Q80W71, Q86VD1, Q86YR7, Q8C5W4

Diamond homologs: B5DF07, O15091, Q4R366, Q8JZY4

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 ribosome-associated quality control	9	12.7×	1e-05
Mitochondrial translation initiation	7	10.2×	7e-04
Mitochondrial translation elongation	7	10.2×	7e-04
Mitochondrial translation termination	7	8.8×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial large ribosomal subunit assembly	5	43.1×	4e-05
mitochondrial translation	8	12.1×	9e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	3
Uncertain significance	69
Likely benign	11
Benign	1

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1879292	GRCh37/hg19 14q13.1-13.3(chr14:34904407-36784136)x1	Pathogenic
4533393	NM_014672.4(PRORP):c.893C>A (p.Ser298Ter)	Pathogenic
1292048	NM_014672.4(PRORP):c.1301C>A (p.Ala434Asp)	Likely pathogenic
4533392	NM_014672.4(PRORP):c.1510C>T (p.His504Tyr)	Likely pathogenic
4849383	NM_014672.4(PRORP):c.1504dup (p.Arg502fs)	Likely pathogenic

SpliceAI

2428 predictions. Top by Δscore:

Variant	Effect	Δscore
14:35121899:CACTG:C	donor_loss	1.0000
14:35121900:A:AC	donor_gain	1.0000
14:35121900:AC:A	donor_loss	1.0000
14:35121901:C:CG	donor_gain	1.0000
14:35121901:CT:C	donor_gain	1.0000
14:35121901:CTG:C	donor_gain	1.0000
14:35121901:CTGT:C	donor_gain	1.0000
14:35126722:A:AG	acceptor_gain	1.0000
14:35126733:A:AG	acceptor_gain	1.0000
14:35126734:G:GG	acceptor_gain	1.0000
14:35126734:GT:G	acceptor_gain	1.0000
14:35127477:A:AG	acceptor_gain	1.0000
14:35127477:AGT:A	acceptor_gain	1.0000
14:35127478:G:GG	acceptor_gain	1.0000
14:35127478:GT:G	acceptor_gain	1.0000
14:35127478:GTG:G	acceptor_gain	1.0000
14:35127609:CAGGT:C	donor_loss	1.0000
14:35127610:AGGT:A	donor_loss	1.0000
14:35127611:GGTG:G	donor_loss	1.0000
14:35127612:GTGA:G	donor_loss	1.0000
14:35127613:T:A	donor_loss	1.0000
14:35180773:AACTT:A	donor_gain	1.0000
14:35180774:ACTT:A	donor_gain	1.0000
14:35180775:CTT:C	donor_gain	1.0000
14:35180775:CTTG:C	donor_loss	1.0000
14:35180775:CTTGT:C	donor_loss	1.0000
14:35180776:TT:T	donor_gain	1.0000
14:35180776:TTG:T	donor_loss	1.0000
14:35180777:TG:T	donor_loss	1.0000
14:35180777:TGT:T	donor_loss	1.0000

AlphaMissense

3853 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:35273540:T:A	W576R	0.993
14:35273540:T:C	W576R	0.993
14:35270534:T:A	W520R	0.992
14:35270534:T:C	W520R	0.992
14:35270455:C:G	C493W	0.990
14:35266859:T:C	F470L	0.989
14:35266861:T:A	F470L	0.989
14:35266861:T:G	F470L	0.989
14:35270430:C:A	A485D	0.989
14:35123617:G:C	W124C	0.988
14:35123617:G:T	W124C	0.988
14:35123615:T:A	W124R	0.987
14:35123615:T:C	W124R	0.987
14:35123921:T:A	W226R	0.986
14:35123921:T:C	W226R	0.986
14:35270408:G:C	D478H	0.986
14:35270536:G:C	W520C	0.986
14:35270536:G:T	W520C	0.986
14:35273542:G:C	W576C	0.986
14:35273542:G:T	W576C	0.986
14:35270466:C:T	T497I	0.984
14:35180722:T:A	V407D	0.983
14:35266776:T:A	V442D	0.983
14:35266785:G:C	R445P	0.983
14:35270410:T:A	D478E	0.981
14:35270410:T:G	D478E	0.981
14:35270538:A:C	Q521P	0.981
14:35270454:G:A	C493Y	0.980
14:35270481:G:C	R502P	0.980
14:35270473:C:A	D499E	0.979

dbSNP variants (sampled 300 via entrez): RS1000001964 (14:35198860 G>A), RS1000021647 (14:35242323 A>C,G), RS1000041774 (14:35267500 G>A), RS1000069722 (14:35153445 G>A), RS1000074790 (14:35197194 A>G), RS1000074891 (14:35133752 C>T), RS1000082066 (14:35178675 G>T), RS1000104067 (14:35147040 A>G), RS1000153808 (14:35155291 G>A,T), RS1000206569 (14:35215923 C>A,T), RS1000242831 (14:35202664 C>A), RS1000245229 (14:35147339 A>T), RS1000259176 (14:35216103 T>A,C), RS1000279556 (14:35261329 C>T), RS1000311431 (14:35254639 G>A,C,T)

Disease associations

OMIM: gene MIM:609947 | disease phenotypes: MIM:233400, MIM:619737

GenCC curated gene-disease

Disease	Classification	Inheritance
combined oxidative phosphorylation deficiency 54	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 (4): Perrault syndrome 1 (MONDO:0009300), combined oxidative phosphorylation deficiency 54 (MONDO:0030543), microcephaly (MONDO:0001149), lactic acidosis (MONDO:0006040)

Orphanet (2): Perrault syndrome (Orphanet:2855), Perrault syndrome type 1 (Orphanet:642945)

HPO phenotypes

45 total (30 of 45 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000233	Thin vermilion border
HP:0000286	Epicanthus
HP:0000308	Microretrognathia
HP:0000316	Hypertelorism
HP:0000407	Sensorineural hearing impairment
HP:0000543	Optic disc pallor
HP:0000709	Psychosis
HP:0000729	Autistic behavior
HP:0000786	Primary amenorrhea
HP:0000815	Hypergonadotropic hypogonadism
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001269	Hemiparesis
HP:0001276	Hypertonia
HP:0001284	Areflexia
HP:0001337	Tremor
HP:0001511	Intrauterine growth retardation
HP:0001513	Obesity
HP:0001649	Tachycardia
HP:0002076	Migraine
HP:0002151	Increased circulating lactate concentration
HP:0002197	Generalized-onset seizure
HP:0002315	Headache
HP:0002354	Memory impairment
HP:0002495	Impaired vibratory sensation
HP:0002650	Scoliosis
HP:0003074	Hyperglycemia
HP:0003326	Myalgia

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST002951_17	Response to zileuton treatment in asthma (FEV1 change interaction)	6.000000e-08
GCST002951_21	Response to zileuton treatment in asthma (FEV1 change interaction)	6.000000e-06
GCST004608_193	Granulocyte percentage of myeloid white cells	2.000000e-10
GCST006606_7	Response to TNF inhibitor in rheumatoid arthritis (change in swollen 28-joint count)	3.000000e-08
GCST009205_13	Supramarginal gyrus volume	8.000000e-06
GCST010988_483	Adult body size	1.000000e-08
GCST012227_586	Hip circumference adjusted for BMI	1.000000e-08
GCST90002398_218	Neutrophil count	6.000000e-15
GCST90002407_619	White blood cell count	6.000000e-16
GCST90020026_235	Hip index	9.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0005921	FEV change measurement
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0004653	response to TNF antagonist
EFO:0005413	joint damage measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0004833	neutrophil count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D000140	Acidosis, Lactic	C18.452.076.176.180
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs12436663	Efficacy	3	zileuton	Asthma

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs12436663	PRORP	3	2.50	1	zileuton

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression	3
Benzo(a)pyrene	affects methylation, decreases expression	3
Cyclosporine	decreases expression, increases expression	2
dicrotophos	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
ochratoxin A	decreases expression	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
corosolic acid	decreases expression	1
jinfukang	decreases expression	1
Acrolein	increases abundance, affects cotreatment, increases oxidation	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Benzophenoneidum	increases expression	1
Doxorubicin	decreases expression	1
Estradiol	decreases expression	1
Folic Acid	decreases expression	1
Methapyrilene	decreases methylation	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Phthalic Acids	increases methylation	1
Quercetin	decreases expression	1
Ribonucleotides	affects binding	1
Rotenone	decreases expression	1
Tunicamycin	decreases expression	1
Urethane	decreases expression	1
Aflatoxin B1	affects expression	1
Cadmium Chloride	decreases expression	1
Thapsigargin	decreases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00202228	PHASE4	COMPLETED	Lactate Metabolism Study in HIV Infected Persons
NCT01354652	PHASE4	TERMINATED	Lactic Acidosis During Entecavir(ETV)Treatment
NCT00004490	PHASE3	COMPLETED	Phase III Randomized Study of Sodium Dichloroacetate in Children With Congenital Lactic Acidosis
NCT00004493	PHASE2	COMPLETED	Phase II Pilot Randomized Study of Sodium Dichloroacetate in Patients With Congenital Lactic Acidemia
NCT01973504	PHASE2	WITHDRAWN	Phase 2c Dose Comparison Study of MP4OX in Trauma
NCT02974257	PHASE2	TERMINATED	Thiamine vs. Placebo to Increase Oxygen Consumption After Cardiac Arrest
NCT03122678	PHASE1	WITHDRAWN	Thiamine Supplementation in Patients With Septic Shock
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.
NCT03466528	PHASE2/PHASE3	COMPLETED	Alcohol: Thiamine and or Magnesium 1
NCT00004353	Not specified	COMPLETED	Study of the Metabolism of Pyruvate and Related Problems in Patients With Lactic Acidemia
NCT00015015	Not specified	COMPLETED	Dichloroacetate Kinetics, Metabolism and Toxicology
NCT00638040	Not specified	WITHDRAWN	The Gene Expression Studies of the Role of Tumor Microenvironments in Tumor Progression
NCT00874276	Not specified	COMPLETED	Pharmacotoxicology of Trichloroethylene Metabolites
NCT00942123	Not specified	COMPLETED	Study On the Role of Mitochondrial Dysfunction in the Pathogenesis of Metformin-associated Lactic Acidosis
NCT01139463	Not specified	COMPLETED	Study of Blood Lactate Levels in Patients Treated With Antipsychotics
NCT01873859	Not specified	COMPLETED	Safety of Continuing Metformin in Diabetic Patients With Normal Kidney Function Receiving Contrast Media
NCT01901419	Not specified	COMPLETED	Nitroglycerin Infusion During Cardiac Surgery
NCT03126890	Not specified	UNKNOWN	Investigation of the Correlation Between Plasma Concentration of Linezolid Antibiotic and Treatment Response and Adverse Reactions
NCT03723993	Not specified	WITHDRAWN	Remote Ischemic Preconditioning During Cardiopulmonary Bypass
NCT04975906	Not specified	COMPLETED	The Threshold of Serum Anion Gap as a Screening Tool for Organic Acidosis
NCT05984186	Not specified	COMPLETED	Effect of High Velocity/Hyperoxic Breathing Therapy on Blood Lactate Decline
NCT06727318	Not specified	COMPLETED	Comparison of Peripheral Perfusion Indicators and Lactate Levels
NCT07193069	Not specified	RECRUITING	Clinical and Biological Signs of Dapagliflozin Overdose in ICU Patients With Metformin Poisoning