PM20D1

Summary

PM20D1 (peptidase M20 domain containing 1, HGNC:26518) is a protein-coding gene on chromosome 1q32.1, encoding N-fatty-acyl-amino acid synthase/hydrolase PM20D1 (Q6GTS8). Secreted enzyme that regulates the endogenous N-fatty acyl amino acid (NAAs) tissue and circulating levels by functioning as a bidirectional NAA synthase/hydrolase.

Enables hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides. Involved in several processes, including amide biosynthetic process; amide catabolic process; and amino acid metabolic process. Located in extracellular exosome.

Source: NCBI Gene 148811 — RefSeq curated summary.

At a glance

• Gene–disease (curated): carbamoyl phosphate synthetase I deficiency disease (Definitive, ClinGen)
• GWAS associations: 176
• Clinical variants (ClinVar): 2,366 total — 113 pathogenic, 247 likely-pathogenic
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_152491

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26518
Approved symbol	PM20D1
Name	peptidase M20 domain containing 1
Location	1q32.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ32569, Cps1
Ensembl gene	ENSG00000162877
Ensembl biotype	protein_coding
OMIM	617124
Entrez	148811

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding_CDS_not_defined, 1 protein_coding

ENST00000367136, ENST00000460624, ENST00000461807, ENST00000469861

RefSeq mRNA: 1 — MANE Select: NM_152491 NM_152491

CCDS: CCDS1460

Canonical transcript exons

ENST00000367136 — 13 exons

Exon	Start	End
ENSE00001373429	205842154	205842215
ENSE00001798148	205828025	205828743
ENSE00001916668	205849904	205850132
ENSE00003461763	205830280	205830379
ENSE00003463211	205844811	205844897
ENSE00003474628	205832598	205832766
ENSE00003584253	205840252	205840323
ENSE00003585418	205844087	205844217
ENSE00003604679	205847885	205847971
ENSE00003617835	205841811	205841889
ENSE00003623592	205843667	205843786
ENSE00003631855	205845325	205845557
ENSE00003652185	205842676	205842751

Expression profiles

Bgee: expression breadth ubiquitous, 144 present calls, max score 98.76.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.0656 / max 237.0410, expressed in 162 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
17043	0.9992	145
17042	0.0664	30

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper leg skin	UBERON:0004262	98.76	gold quality
upper arm skin	UBERON:0004263	95.17	gold quality
mammalian vulva	UBERON:0000997	94.66	gold quality
body of pancreas	UBERON:0001150	93.04	gold quality
pancreas	UBERON:0001264	82.40	gold quality
tibialis anterior	UBERON:0001385	75.71	silver quality
epithelial cell of pancreas	CL:0000083	73.91	gold quality
pancreatic ductal cell	CL:0002079	73.14	silver quality
ileal mucosa	UBERON:0000331	72.57	silver quality
skin of abdomen	UBERON:0001416	69.40	gold quality
granulocyte	CL:0000094	66.39	gold quality
zone of skin	UBERON:0000014	66.29	gold quality
nipple	UBERON:0002030	66.27	gold quality
islet of Langerhans	UBERON:0000006	65.84	gold quality
body of stomach	UBERON:0001161	65.79	gold quality
apex of heart	UBERON:0002098	65.38	gold quality
stomach	UBERON:0000945	63.05	gold quality
adult mammalian kidney	UBERON:0000082	62.79	gold quality
deltoid	UBERON:0001476	61.36	gold quality
urinary bladder	UBERON:0001255	61.00	gold quality
skin of leg	UBERON:0001511	60.77	gold quality
mucosa of stomach	UBERON:0001199	60.63	gold quality
sural nerve	UBERON:0015488	59.52	silver quality
lymph node	UBERON:0000029	59.10	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	58.78	gold quality
right atrium auricular region	UBERON:0006631	58.46	gold quality
kidney	UBERON:0002113	58.44	gold quality
cardiac atrium	UBERON:0002081	57.98	gold quality
colonic epithelium	UBERON:0000397	57.96	silver quality
tibial nerve	UBERON:0001323	57.47	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-2	yes	6071.37
E-ANND-3	yes	18.49
E-ENAD-17	no	62.85

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

49 targeting PM20D1, 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-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-4716-3P	99.69	66.73	1022
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-4762-5P	99.57	68.54	1424
HSA-MIR-4519	99.48	66.10	859
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-148A-5P	99.30	68.27	1141
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-6071	99.16	67.77	1780
HSA-MIR-4504	99.10	69.14	1328
HSA-MIR-3168	99.08	67.75	1384
HSA-MIR-628-3P	99.04	68.37	814
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-4709-3P	98.88	68.04	1594
HSA-MIR-6796-3P	98.68	65.49	689
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-3136-5P	98.53	67.68	793

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 7)

• These findings suggest that in a particular genetic background, PM20D1 contributes to neuroprotection against Alzheimer’s disease. (PMID:29736028)
• upstream variant determines PPARgamma regulation of PM20D1 in adipocytes; distinct variants downstream of the transcription start site have strong effects on PM20D1 expression in human fat as well as other tissues (PMID:31659023)
• Comprehensive analysis of PM20D1 QTL in Alzheimer’s disease. (PMID:32014019)
• Cooperative enzymatic control of N-acyl amino acids by PM20D1 and FAAH. (PMID:32271712)
• Longitudinal data in peripheral blood confirm that PM20D1 is a quantitative trait locus (QTL) for Alzheimer’s disease and implicate its dynamic role in disease progression. (PMID:33298155)
• PM20D1 is a circulating biomarker closely associated with obesity, insulin resistance and metabolic syndrome. (PMID:34757919)
• Clinical Significance of Peptidase M20 Domain Containing 1 Ii Patients with Carotid Atherosclerosis.", trans “Significado Clinico do Dominio da Peptidase M20 Contendo 1 em Pacientes com Aterosclerose Carotidea. (PMID:35544855)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	pm20d1.1	ENSDARG00000037551
danio_rerio	pm20d1.2	ENSDARG00000062096
mus_musculus	Pm20d1	ENSMUSG00000042251
rattus_norvegicus	Pm20d1	ENSRNOG00000039745

Paralogs (3): CNDP2 (ENSG00000133313), CNDP1 (ENSG00000150656), ACY1 (ENSG00000243989)

Protein

Protein identifiers

N-fatty-acyl-amino acid synthase/hydrolase PM20D1 — Q6GTS8 (reviewed: Q6GTS8)

Alternative names: Peptidase M20 domain-containing protein 1

All UniProt accessions (1): Q6GTS8

UniProt curated annotations — full annotation on UniProt →

Function. Secreted enzyme that regulates the endogenous N-fatty acyl amino acid (NAAs) tissue and circulating levels by functioning as a bidirectional NAA synthase/hydrolase. It condenses free fatty acids and free amino acids to generate NAAs and bidirectionally catalyzes the reverse hydrolysis reaction. Some of these NAAs stimulate oxidative metabolism via mitochondrial uncoupling, increasing energy expenditure in a UPC1-independent manner. Thereby, this secreted protein may indirectly regulate whole body energy expenditure. PM20D1 circulates in tight association with both low- and high-density (LDL and HDL,respectively) lipoprotein particles.

Subcellular location. Secreted.

Activity regulation. Lipoproteins are powerful coactivators of PM20D1 activity in vitro and NAA biosynthesis in vivo.

Cofactor. Binds 2 Zn(2+) ions per subunit.

Pathway. Amino-acid metabolism. Energy metabolism. Lipid metabolism; fatty acid metabolism.

Miscellaneous. Genetically increasing or decreasing the expression of PM20D1 reduces and aggravates Alzheimer’s disease (AD) related pathologies, respectively. These findings suggest that in a particular genetic background, PM20D1 contributes to neuroprotection against AD.

Similarity. Belongs to the peptidase M20A family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6GTS8-1	1	yes
Q6GTS8-2	2

RefSeq proteins (1): NP_689704* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002933	Peptidase_M20	Family
IPR011650	Peptidase_M20_dimer	Domain
IPR036264	Bact_exopeptidase_dim_dom	Homologous_superfamily
IPR047177	Pept_M20A	Family

Pfam: PF01546, PF07687

Catalyzed reactions (Rhea), 12 shown:

• an N-acyl-L-amino acid + H2O = an L-alpha-amino acid + a carboxylate (RHEA:15565)
• L-phenylalanine + (9Z)-octadecenoate = N-(9Z-octadecenoyl)-L-phenylalanine + H2O (RHEA:51300)
• (5Z,8Z,11Z,14Z)-eicosatetraenoate + L-phenylalanine = N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-L-phenylalanine + H2O (RHEA:51312)
• (9Z)-octadecenoate + glycine = N-(9Z-octadecenoyl)glycine + H2O (RHEA:51316)
• N-(9Z-octadecenoyl)-L-serine + H2O = L-serine + (9Z)-octadecenoate (RHEA:51352)
• N-(9Z-octadecenoyl)-L-glutamine + H2O = L-glutamine + (9Z)-octadecenoate (RHEA:51356)
• N-(9Z-octadecenoyl)-L-leucine + H2O = L-leucine + (9Z)-octadecenoate (RHEA:51360)
• an N-acyl-aromatic L-alpha-amino acid + H2O = an aromatic L-alpha-amino acid + a carboxylate (RHEA:54184)
• N-(5Z,8Z,11Z,14Z)-eicosatetraenoyl-glycine + H2O = (5Z,8Z,11Z,14Z)-eicosatetraenoate + glycine (RHEA:64108)
• N-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-L-serine + H2O = (5Z,8Z,11Z,14Z)-eicosatetraenoate + L-serine (RHEA:64116)
• N-hexadecanoyl-L-phenylalanine + H2O = hexadecanoate + L-phenylalanine (RHEA:64124)
• N-octadecanoyl-L-phenylalanine + H2O = octadecanoate + L-phenylalanine (RHEA:64128)

UniProt features (21 total): sequence variant 7, binding site 6, splice variant 2, active site 2, signal peptide 1, chain 1, glycosylation site 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6GTS8-F1	89.55	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.

Catalytic / active sites (2): 127; 191 (proton acceptor)

Ligand- & substrate-binding residues (6): 125; 157; 157; 192; 217; 464

Glycosylation sites (1): 252

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9673163	Oleoyl-phe metabolism

MSigDB gene sets: 365 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_RESPONSE_TO_ZINC_ION, YAGI_AML_WITH_INV_16_TRANSLOCATION, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_RESPONSE_TO_AMINE, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_RESPONSE_TO_CORTICOSTEROID, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_RESPONSE_TO_FOOD

GO Biological Process (8): proteolysis (GO:0006508), amino acid metabolic process (GO:0006520), lipid metabolic process (GO:0006629), fatty acid metabolic process (GO:0006631), obsolete amide biosynthetic process (GO:0043604), obsolete amide catabolic process (GO:0043605), energy homeostasis (GO:0097009), adaptive thermogenesis (GO:1990845)

GO Molecular Function (6): aminoacylase activity (GO:0004046), peptidase activity (GO:0008233), hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides (GO:0016811), lyase activity (GO:0016829), metal ion binding (GO:0046872), hydrolase activity (GO:0016787)

GO Cellular Component (3): extracellular region (GO:0005576), extracellular exosome (GO:0070062), obsolete extracellular space (GO:0005615)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Mitochondrial Uncoupling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
primary metabolic process	2
catalytic activity	2
protein metabolic process	1
lipid metabolic process	1
monocarboxylic acid metabolic process	1
multicellular organismal-level homeostasis	1
temperature homeostasis	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides	1
hydrolase activity	1
catalytic activity, acting on a protein	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds	1
cation binding	1
cellular anatomical structure	1
extracellular vesicle	1

Protein interactions and networks

STRING

1666 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PM20D1	NUCKS1	Q9H1E3	927
PM20D1	SLC41A1	Q8IVJ1	923
PM20D1	RAB29	O14966	922
PM20D1	SLC45A3	Q96JT2	808
PM20D1	SPATC1L	Q9H0A9	626
PM20D1	LRRK2	Q5S007	617
PM20D1	MAPT	P10636	512
PM20D1	SNCA	P37840	510
PM20D1	SLC17A3	O00476	468
PM20D1	KRTCAP3	Q53RY4	461
PM20D1	UCP1	P25874	447
PM20D1	PM20D2	Q8IYS1	428
PM20D1	SPINK9	Q5DT21	416
PM20D1	SEPTIN8	Q92599	410
PM20D1	FKBP5	Q13451	408

IntAct

12 interactions, top by confidence:

A	B	Type	Score
NPPA	A2ML1	psi-mi:“MI:0914”(association)	0.530
PDE4DIP	A2ML1	psi-mi:“MI:0914”(association)	0.350
MBD4	A2ML1	psi-mi:“MI:0914”(association)	0.350
ST7	A2ML1	psi-mi:“MI:0914”(association)	0.350
MRM1	RIMOC1	psi-mi:“MI:0914”(association)	0.350
SH2D3A	A2ML1	psi-mi:“MI:0914”(association)	0.350
PINK1	A2ML1	psi-mi:“MI:0914”(association)	0.350
PCP4	A2ML1	psi-mi:“MI:0914”(association)	0.350
UPK1A	A2ML1	psi-mi:“MI:0914”(association)	0.350
NT5C1A	A2ML1	psi-mi:“MI:0914”(association)	0.350

BioGRID (14): PM20D1 (Affinity Capture-MS), PM20D1 (Affinity Capture-MS), PM20D1 (Affinity Capture-MS), PM20D1 (Affinity Capture-MS), PM20D1 (Affinity Capture-MS), PM20D1 (Affinity Capture-MS), PM20D1 (Affinity Capture-MS), PM20D1 (Affinity Capture-MS), PM20D1 (Affinity Capture-MS), PM20D1 (Affinity Capture-MS), PM20D1 (Affinity Capture-MS), PM20D1 (Affinity Capture-MS), PM20D1 (Affinity Capture-MS), PM20D1 (Affinity Capture-RNA)

ESM2 similar proteins: A0A1I9LN01, A4VY21, A4W4B4, A5VJ57, A8YUT2, B2G6M8, I1L153, O04373, O34980, O49434, O64749, O74197, O74916, O81641, O94266, P40386, P54968, P54969, P54970, P55663, Q03YE3, Q04FS2, Q08BB2, Q08BT9, Q1WUQ7, Q2QMN7, Q2T9M7, Q32LT9, Q3SY69, Q40546, Q4LB35, Q5FKR0, Q655X8, Q6GTS8, Q7XUA8, Q84XG9, Q851L5, Q851L6, Q8C165, Q8DVY6

Diamond homologs: A4WG54, A5F4Z7, A5IG28, A6Q4D7, A7FCZ8, A7MXC2, A7ZUH5, A8A765, A9MI13, A9N0G7, B0RW53, B0U296, B1IVC1, B1LNR7, B1XBC2, B2FIC0, B2I6B4, B2SQY5, B2TWF2, B2VGA3, B4F192, B4SQ35, B4T0W8, B4TCQ3, B4TQH3, B5BJN1, B5F0U6, B5FBP7, B5FPX2, B5QXQ2, B5RF48, B5XZ19, B5Z059, B6EMN5, B6I5H3, B7LA57, B7LUN8, B7M711, B7MI93, B7MR48

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

2366 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	113
Likely pathogenic	247
Uncertain significance	583
Likely benign	1072
Benign	124

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1001895	NM_001875.5(CPS1):c.1141_1149del (p.Thr381_Gly383del)	Pathogenic
1068809	NM_001875.5(CPS1):c.2051C>G (p.Ser684Ter)	Pathogenic
1069202	NM_001875.5(CPS1):c.1432C>T (p.Gln478Ter)	Pathogenic
1070017	NC_000002.11:g.(?211421433)(211421593_?)del	Pathogenic
1070018	NC_000002.11:g.(?211441050)(211542729_?)del	Pathogenic
1071808	NM_001875.5(CPS1):c.2171_2175del (p.Ala724fs)	Pathogenic
1072514	NM_001875.5(CPS1):c.2470_2482del (p.Thr824fs)	Pathogenic
1076647	NM_001875.5(CPS1):c.3520C>T (p.Arg1174Ter)	Pathogenic
1076733	NM_001875.5(CPS1):c.1112del (p.Phe371fs)	Pathogenic
1076846	NM_001875.5(CPS1):c.3763G>T (p.Glu1255Ter)	Pathogenic
1172776	NM_001875.5(CPS1):c.1164+2T>C	Pathogenic
1192241	NM_001875.5(CPS1):c.2798del (p.Arg932_Leu933insTer)	Pathogenic
1321400	NM_001875.5(CPS1):c.1770T>G (p.Tyr590Ter)	Pathogenic
1381784	NM_001875.5(CPS1):c.3666+1G>T	Pathogenic
1408700	NM_001875.5(CPS1):c.1509del (p.Gly503_Leu504insTer)	Pathogenic
1435669	NM_001875.5(CPS1):c.2408dup (p.Thr804fs)	Pathogenic
1444282	NC_000002.12:g.210577425_210577431del	Pathogenic
1452254	NM_001875.5(CPS1):c.3307C>T (p.Gln1103Ter)	Pathogenic
1453334	NM_001875.5(CPS1):c.4159A>T (p.Lys1387Ter)	Pathogenic
1454065	NM_001875.5(CPS1):c.3935dup (p.Met1312fs)	Pathogenic
1455500	NM_001875.5(CPS1):c.1468C>T (p.Gln490Ter)	Pathogenic
1455517	NC_000002.11:g.(?211512577)(211513274_?)del	Pathogenic
1455929	NM_001875.5(CPS1):c.2876_2877del (p.Tyr959fs)	Pathogenic
1457203	NM_001875.5(CPS1):c.3216del (p.Val1073fs)	Pathogenic
1458288	NM_001875.5(CPS1):c.2446del (p.Cys816fs)	Pathogenic
1486720	NM_001875.5(CPS1):c.3266G>T (p.Arg1089Leu)	Pathogenic
1685668	NM_001875.5(CPS1):c.345_351del (p.Gly116fs)	Pathogenic
1685669	NM_001875.5(CPS1):c.4275-2A>C	Pathogenic
1935741	NM_001875.5(CPS1):c.2477del (p.Arg826fs)	Pathogenic
1940644	NM_001875.5(CPS1):c.1221_1222del (p.Val409fs)	Pathogenic

SpliceAI

2434 predictions. Top by Δscore:

Variant	Effect	Δscore
1:205829979:C:CT	acceptor_gain	1.0000
1:205829979:C:T	acceptor_gain	1.0000
1:205830380:C:CC	acceptor_gain	1.0000
1:205832770:C:CT	acceptor_gain	1.0000
1:205832771:A:T	acceptor_gain	1.0000
1:205832774:G:GC	acceptor_gain	1.0000
1:205840319:TTGAA:T	acceptor_gain	1.0000
1:205840324:C:CC	acceptor_gain	1.0000
1:205841805:TGTTA:T	donor_loss	1.0000
1:205841806:GTTAC:G	donor_loss	1.0000
1:205841807:TTA:T	donor_loss	1.0000
1:205841808:TA:T	donor_loss	1.0000
1:205841809:A:AG	donor_loss	1.0000
1:205841812:TTG:T	donor_gain	1.0000
1:205841887:AACC:A	acceptor_loss	1.0000
1:205841888:ACCTA:A	acceptor_loss	1.0000
1:205841889:CCTAA:C	acceptor_loss	1.0000
1:205841890:CT:C	acceptor_loss	1.0000
1:205841891:T:A	acceptor_loss	1.0000
1:205842670:CCATA:C	donor_loss	1.0000
1:205842671:CATA:C	donor_loss	1.0000
1:205842672:ATACC:A	donor_loss	1.0000
1:205842673:TA:T	donor_loss	1.0000
1:205842675:C:CG	donor_loss	1.0000
1:205842747:CCAAT:C	acceptor_gain	1.0000
1:205842748:CAAT:C	acceptor_gain	1.0000
1:205842748:CAATC:C	acceptor_gain	1.0000
1:205842751:TCT:T	acceptor_loss	1.0000
1:205842752:C:CC	acceptor_gain	1.0000
1:205842753:T:C	acceptor_loss	1.0000

AlphaMissense

3294 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:205828726:T:A	E468V	0.990
1:205840280:C:G	R363P	0.989
1:205840296:C:G	A358P	0.986
1:205845408:A:G	W136R	0.984
1:205845408:A:T	W136R	0.984
1:205845406:C:A	W136C	0.983
1:205845406:C:G	W136C	0.983
1:205845337:C:A	K159N	0.981
1:205845337:C:G	K159N	0.981
1:205841848:G:A	T336I	0.980
1:205845391:G:C	F141L	0.980
1:205845391:G:T	F141L	0.980
1:205845393:A:G	F141L	0.980
1:205828726:T:G	E468A	0.978
1:205832683:G:C	S400R	0.977
1:205832683:G:T	S400R	0.977
1:205832685:T:G	S400R	0.977
1:205845343:G:C	D157E	0.977
1:205845343:G:T	D157E	0.977
1:205840301:G:T	A356D	0.976
1:205843685:A:T	L270H	0.976
1:205832726:A:T	V386D	0.974
1:205843677:C:G	A273P	0.974
1:205845344:T:A	D157V	0.974
1:205843754:A:G	L247P	0.972
1:205845353:C:A	G154V	0.971
1:205845499:G:C	S105R	0.971
1:205845499:G:T	S105R	0.971
1:205845501:T:G	S105R	0.971
1:205828725:C:A	E468D	0.970

dbSNP variants (sampled 300 via entrez): RS1000119022 (1:205828713 G>C,T), RS1000128678 (1:205831787 C>T), RS1000215906 (1:205833911 G>A,C), RS1000249845 (1:205831546 T>A), RS1000414162 (1:205847513 G>A), RS1000652598 (1:205841322 A>G), RS1000887660 (1:205852004 C>T), RS1001413641 (1:205845583 A>G), RS1001518907 (1:205844868 C>G,T), RS1001656243 (1:205832703 A>G,T), RS1001666588 (1:205851507 A>G), RS1001718602 (1:205851310 C>A), RS1002211857 (1:205838461 C>G,T), RS1002326141 (1:205838141 AG>A), RS1002368972 (1:205839585 T>C)

Disease associations

OMIM: gene MIM:617124 | disease phenotypes: MIM:237300, MIM:615371

GenCC curated gene-disease

Disease	Classification	Inheritance
carbamoyl phosphate synthetase I deficiency disease	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
carbamoyl phosphate synthetase I deficiency disease	Definitive	AR

Mondo (4): carbamoyl phosphate synthetase I deficiency disease (MONDO:0009376), pulmonary hypertension, neonatal, susceptibility to (MONDO:0014151), hereditary breast ovarian cancer syndrome (MONDO:0003582), intellectual disability (MONDO:0001071)

Orphanet (3): Carbamoyl-phosphate synthetase 1 deficiency (Orphanet:147), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

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

GWAS associations

176 associations (top):

Study	Trait	p-value
GCST000368_3	Fibrinogen	9.000000e-09
GCST000530_4	Parkinson’s disease	2.000000e-12
GCST000594_1	Homocysteine levels	5.000000e-09
GCST000649_25	Chronic kidney disease	1.000000e-15
GCST001217_2	Metabolic traits	2.000000e-27
GCST001734_4	Non-small cell lung cancer	3.000000e-06
GCST001796_1	Prostate-specific antigen levels	2.000000e-19
GCST001852_3	Metabolite levels	3.000000e-50
GCST001945_6	Body mass index in asthmatics	9.000000e-06
GCST002087_3	Homocysteine levels	5.000000e-27
GCST002147_5	Fibrinogen	2.000000e-11
GCST002223_25	HDL cholesterol	9.000000e-10
GCST002388_6	Serum metabolite levels	4.000000e-12
GCST002391_5	Plasma homocysteine levels (post-methionine load test)	9.000000e-13
GCST002783_160	Body mass index	7.000000e-06
GCST002783_213	Body mass index	4.000000e-06
GCST002813_15	Alzheimer’s disease in APOE e4+ carriers	4.000000e-06
GCST002828_14	Urate levels in obese individuals	3.000000e-06
GCST003119_1	Urinary metabolites	8.000000e-31
GCST003119_12	Urinary metabolites	3.000000e-25
GCST003194_2	Fibrinogen levels	4.000000e-16
GCST003358_2	Betaine levels in individuals undergoing cardiac evaluation	1.000000e-08
GCST003372_12	Glomerular filtration rate (creatinine)	2.000000e-23
GCST003374_3	Chronic kidney disease	8.000000e-09
GCST003401_2	Glomerular filtration rate in non diabetics (creatinine)	3.000000e-22
GCST003790_16	Glomerular filtration rate	1.000000e-11
GCST004121_22	Fibrinogen levels	2.000000e-13
GCST004122_15	Fibrinogen levels	9.000000e-14
GCST004171_2	Macular telangiectasia type 2	1.000000e-15
GCST004292_11	Glomerular filtration rate (creatinine)	2.000000e-16

EFO canonical traits (42, from GWAS)

EFO ID	Trait name
EFO:0004578	homocysteine measurement
EFO:0004725	metabolite measurement
EFO:0004471	insulin sensitivity measurement
EFO:0004340	body mass index
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004531	urate measurement
EFO:0005116	urinary metabolite measurement
EFO:0007787	plasma betaine measurement
EFO:1002009	macular telangiectasia type 2
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004309	platelet count
EFO:0007985	platelet crit
EFO:0007996	eosinophil percentage of granulocytes
EFO:0004527	mean corpuscular hemoglobin
EFO:0004285	albuminuria
EFO:0006335	systolic blood pressure
EFO:0005134	amino acid measurement
EFO:0009767	glycine measurement
EFO:0006524	L-arginine measurement
EFO:0009777	citrulline measurement
EFO:0009768	glutamine measurement
EFO:0009774	serine measurement
EFO:0009775	threonine measurement
EFO:0006946	behavioural disinhibition measurement
EFO:0009882	urinary potassium to creatinine ratio
EFO:0004761	uric acid measurement
EFO:0009883	urinary sodium to creatinine ratio
EFO:0004329	alcohol drinking
EFO:0007778	urinary albumin to creatinine ratio
EFO:0004614	apolipoprotein A 1 measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D020165	Carbamoyl-Phosphate Synthase I Deficiency Disease	C10.228.140.163.100.937.249; C16.320.565.100.940.249; C16.320.565.189.937.249; C18.452.132.100.937.249; C18.452.648.100.940.249; C18.452.648.189.937.249; C18.452.660.097
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation	2
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
benzo(e)pyrene	increases methylation	1
Sunitinib	decreases expression	1
Cadmium	decreases expression, increases abundance	1
Methapyrilene	increases methylation	1
Tetrachlorodibenzodioxin	decreases expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00673335	PHASE3	COMPLETED	Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
NCT00685256	PHASE3	COMPLETED	Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children
NCT03162276	PHASE3	UNKNOWN	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00718627	PHASE2	COMPLETED	Human Heterologous Liver Cells for Infusion in Children With Urea Cycle Disorders
NCT00475904	PHASE2	COMPLETED	A Comparison of EpiCept™ NP-1 Topical Cream vs. Oral Gabapentin in Postherpetic Neuralgia (PHN)
NCT00253539	PHASE2	COMPLETED	Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer
NCT00305695	PHASE2	COMPLETED	Zoledronate or Observation in Maintaining Bone Mineral Density in Patients Who Are Undergoing Surgery to Remove Both Ovaries
NCT00321633	PHASE2	COMPLETED	Carboplatin or Docetaxel in Treating Women With Metastatic Genetic Breast Cancer
NCT01333748	PHASE2	COMPLETED	Search Allelic Imbalance of Expression of BRCA Genes in Hereditary Risk of Breast and/or Ovarian Cancer
NCT01367639	PHASE2	COMPLETED	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00535119	PHASE1	COMPLETED	Veliparib, Carboplatin, and Paclitaxel in Treating Patients With Advanced Solid Cancer
NCT00892736	PHASE1	COMPLETED	Veliparib in Treating Patients With Malignant Solid Tumors That Do Not Respond to Previous Therapy
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05910151	Not specified	UNKNOWN	Selective Screening of Children for Hereditary Metabolic Diseases by Tandem Mass Spectrometry in Kazakhstan
NCT03832985	EARLY_PHASE1	COMPLETED	Pediatric Reporting of Adult-Onset Genomic Results
NCT00005095	Not specified	RECRUITING	Specimen and Data Study for Ovarian Cancer Early Detection and Prevention
NCT00609505	Not specified	COMPLETED	Telemedicine vs. Face-to-Face Cancer Genetic Counseling
NCT01273909	Not specified	UNKNOWN	Outcomes After Perforator Flap Reconstruction for Breast Reconstruction and/or Lymphedema Treatment
NCT01445275	Not specified	WITHDRAWN	Cost of Cancer Risk Management in Women at Elevated Genetic Risk for Ovarian Cancer Who Participated on GOG-0199
NCT01608074	Not specified	ACTIVE_NOT_RECRUITING	Radical Fimbriectomy for Young BRCA Mutation Carriers
NCT02087592	Not specified	COMPLETED	Feasibility of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02302742	Not specified	RECRUITING	Triple Negative Breast Cancer and Germline Hereditary Breast and Ovarian Cancer Mutation Carrier Registry
NCT02324062	Not specified	COMPLETED	Cancer Genetics Hereditary Cancer Panel Testing
NCT02516540	Not specified	UNKNOWN	Efficacy of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02653105	Not specified	ACTIVE_NOT_RECRUITING	Women at Risk of Breast Cancer and OLFM4