PRIM1

Summary

PRIM1 (DNA primase subunit 1, HGNC:9369) is a protein-coding gene on chromosome 12q13.3, encoding DNA primase small subunit (P49642). Catalytic subunit of the DNA primase complex and component of the DNA polymerase alpha complex (also known as the alpha DNA polymerase-primase complex - primosome/replisome) which play an essential role in the initiation of DNA synthesis. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

The replication of DNA in eukaryotic cells is carried out by a complex chromosomal replication apparatus, in which DNA polymerase alpha and primase are two key enzymatic components. Primase, which is a heterodimer of a small subunit and a large subunit, synthesizes small RNA primers for the Okazaki fragments made during discontinuous DNA replication. The protein encoded by this gene is the small, 49 kDa primase subunit.

Source: NCBI Gene 5557 — RefSeq curated summary.

At a glance

• Gene–disease (curated): primordial dwarfism-immunodeficiency-lipodystrophy syndrome (Strong, GenCC)
• GWAS associations: 17
• Clinical variants (ClinVar): 58 total — 3 pathogenic
• Phenotypes (HPO): 58
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_000946

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9369
Approved symbol	PRIM1
Name	DNA primase subunit 1
Location	12q13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000198056
Ensembl biotype	protein_coding
OMIM	176635
Entrez	5557

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 6 protein_coding, 2 protein_coding_CDS_not_defined, 2 retained_intron, 2 nonsense_mediated_decay

ENST00000338193, ENST00000546761, ENST00000548173, ENST00000549549, ENST00000550224, ENST00000550770, ENST00000552408, ENST00000552590, ENST00000672280, ENST00000706566, ENST00000706567, ENST00000859895

RefSeq mRNA: 1 — MANE Select: NM_000946 NM_000946

CCDS: CCDS44926

Canonical transcript exons

ENST00000338193 — 13 exons

Exon	Start	End
ENSE00001422346	56746045	56746181
ENSE00001429460	56746781	56746854
ENSE00002383787	56731580	56731734
ENSE00002392700	56752196	56752323
ENSE00003476405	56751038	56751195
ENSE00003490419	56739294	56739363
ENSE00003512221	56742987	56743096
ENSE00003560894	56741435	56741576
ENSE00003575614	56734147	56734245
ENSE00003614337	56741746	56741837
ENSE00003632994	56738434	56738525
ENSE00003638545	56744065	56744123
ENSE00003691409	56746926	56747032

Expression profiles

Bgee: expression breadth ubiquitous, 137 present calls, max score 93.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.0247 / max 631.1291, expressed in 1657 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
131601	20.8646	1608
131602	2.1601	987

Top tissues by expression

148 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	93.17	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.77	gold quality
ganglionic eminence	UBERON:0004023	89.35	gold quality
ventricular zone	UBERON:0003053	88.82	gold quality
bone marrow	UBERON:0002371	84.86	gold quality
cortical plate	UBERON:0005343	84.65	gold quality
bone marrow cell	CL:0002092	84.12	gold quality
rectum	UBERON:0001052	83.53	gold quality
calcaneal tendon	UBERON:0003701	83.08	gold quality
lymph node	UBERON:0000029	82.76	gold quality
islet of Langerhans	UBERON:0000006	81.22	gold quality
corpus callosum	UBERON:0002336	81.15	gold quality
right testis	UBERON:0004534	81.15	gold quality
testis	UBERON:0000473	81.02	gold quality
leukocyte	CL:0000738	80.81	gold quality
vermiform appendix	UBERON:0001154	80.75	gold quality
monocyte	CL:0000576	80.64	gold quality
granulocyte	CL:0000094	79.76	gold quality
endometrium	UBERON:0001295	79.70	gold quality
left testis	UBERON:0004533	79.46	gold quality
tonsil	UBERON:0002372	78.68	gold quality
smooth muscle tissue	UBERON:0001135	78.62	gold quality
pancreas	UBERON:0001264	78.59	gold quality
body of pancreas	UBERON:0001150	78.03	gold quality
blood	UBERON:0000178	77.24	gold quality
hindlimb stylopod muscle	UBERON:0004252	76.88	gold quality
placenta	UBERON:0001987	76.76	gold quality
cerebellar cortex	UBERON:0002129	76.40	gold quality
cerebellar hemisphere	UBERON:0002245	76.34	gold quality
cerebellum	UBERON:0002037	76.02	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.56

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

23 targeting PRIM1, 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-3658	99.96	73.87	4379
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-6126	99.62	68.09	996
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-514B-5P	99.50	68.19	1766
HSA-MIR-642A-3P	99.23	67.67	1258
HSA-MIR-642B-3P	99.23	67.67	1258
HSA-MIR-4727-5P	99.23	67.55	1154
HSA-MIR-6738-3P	99.03	67.14	1326
HSA-MIR-6830-5P	99.01	68.73	1884
HSA-MIR-4635	98.74	67.63	1339
HSA-MIR-1910-3P	98.44	67.51	1695
HSA-MIR-561-5P	98.25	68.13	1365
HSA-MIR-6511A-5P	98.13	67.47	1770
HSA-MIR-4769-3P	97.95	68.17	1002
HSA-MIR-6817-5P	97.95	67.86	1026
HSA-MIR-8057	97.64	66.54	897
HSA-MIR-148B-5P	97.29	66.30	992
HSA-MIR-6874-3P	97.29	66.34	975

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 11)

• Mechanisms by which human DNA primase chooses to polymerize a nucleoside triphosphate (PMID:20030400)
• Findings indicate that tethering of DNA primase Prim1 to the replisome by DNA polymerase alpha (pol alpha) is critical for the normal action of DNA replication forks in eukaryotic cells. (PMID:22593576)
• Data indicate that the conformational changes in primase are necessary to accomplish the initiation and then elongation of RNA synthesis. (PMID:25550159)
• Data suggest that PRIM1-p58,C-terminal domain stays bound to initiating NTP and 3prime-overhang DNA during whole cycle of RNA primer synthesis; meanwhile, PRIM1-p49 slides along DNA template toward 5prime-end with PRIM1-p58,N-terminal domain attached. (PMID:26710848)
• No mutations within PRIM1 were found in Chinese women with primary ovarian insufficiency. (PMID:27599756)
• PRIM1 was detected preferentially at a higher level (>40-fold) in poorly differentiated tumor tissues (n = 46) compared with more highly differentiated tumors tissues (n = 10) (*p = 0.005). (PMID:30097999)
• PRIM1 inactivation sensitizes cancer cells to ATR and CHK1 inhibitors via S-phase stasis and Wee1-mediated, caspase 8-dependent apoptosis. (PMID:30257222)
• the structure of human p49at 2.2A resolution with citrate in its inactive forms, is reported. (PMID:30446220)
• DNA Primase Subunit 1 Expression in Hepatocellular Carcinoma and Its Clinical Implication. (PMID:32908930)
• Small tandem DNA duplications result from CST-guided Pol alpha-primase action at DNA break termini. (PMID:34376693)
• Variable Syndromic Immunodeficiency in Patients with Biallelic PRIM1 Mutations. (PMID:38773012)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	prim1	ENSDARG00000040163
mus_musculus	Prim1	ENSMUSG00000025395
rattus_norvegicus	Prim1	ENSRNOG00000031993
rattus_norvegicus		ENSRNOG00000086012
drosophila_melanogaster	Prim1	FBGN0011762
caenorhabditis_elegans		WBGENE00004180
caenorhabditis_elegans		WBGENE00020761

Protein

Protein identifiers

DNA primase small subunit — P49642 (reviewed: P49642)

Alternative names: DNA primase 49 kDa subunit

All UniProt accessions (6): A0A5F9ZHB6, A0A9L9PXM3, F8VNY2, F8VSB2, P49642, H0YIP2

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of the DNA primase complex and component of the DNA polymerase alpha complex (also known as the alpha DNA polymerase-primase complex - primosome/replisome) which play an essential role in the initiation of DNA synthesis. During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1, an accessory subunit POLA2 and two primase subunits, the catalytic subunit PRIM1 and the regulatory subunit PRIM2) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1. The primase subunit of the polymerase alpha complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands. These primers are initially extended by the polymerase alpha catalytic subunit and subsequently transferred to polymerase delta and polymerase epsilon for processive synthesis on the lagging and leading strand, respectively. In the primase complex, both subunits are necessary for the initial di-nucleotide formation, but the extension of the primer depends only on the catalytic subunit. Synthesizes 9-mer RNA primers (also known as the ‘unit length’ RNA primers). Incorporates only ribonucleotides in the presence of ribo- and deoxy-nucleotide triphosphates (rNTPs, dNTPs). Requires template thymine or cytidine to start the RNA primer synthesis, with an adenine or guanine at its 5’-end. Binds single stranded DNA.

Subunit / interactions. Heterodimer of a catalytic subunit PRIM1 and a regulatory subunit PRIM2, also known as the DNA primase complex. Interacts with PRIM2 (via C-terminus). Component of the alpha DNA polymerase complex (also known as the alpha DNA polymerase-primase complex) consisting of four subunits: the catalytic subunit POLA1, the regulatory subunit POLA2, and the primase complex subunits PRIM1 and PRIM2 respectively. Within the complex, POLA1 directly interacts with PRIM2.

Disease relevance. Primordial dwarfism-immunodeficiency-lipodystrophy syndrome (PDIL) [MIM:620005] An autosomal recessive syndrome characterized by growth failure with in utero growth retardation and severe postnatal growth restriction, severe microcephaly, absence of subcutaneous fat, and significant haematological and immune dysfunction. Patients have hypo- or agammaglobulinemia, lymphopenia, anemia, and thrombocytopenia. Most affected individuals die in early childhood from either respiratory or gastrointestinal infections. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. The presence of the regulatory subunit PRIM2/p58 accelerates the kinetics of initiation and primer extension. Inhibited by arabinose nucleoside derivatives such as fludarabine and vidarabine.

Domain organisation. The catalytic domain (residues 1-190 and 303-408) adopts a typical ‘prim’ fold structure formed by two three strand beta-sheets that line the inside of the lower and upper parts, each surrounded by alpha-helices on the outside. It comprises a highly conserved catalytic triad, a structural zinc-binding motif and the nucleotide-binding motifs. The Asp-109, Asp-111 and Asp-306 catalytic triad binds two Mn2+ or Mg2+ ions which activate for nucleophilic attack the 3’-hydroxyl of the growing RNA primer or of the first NTP bound at the initiation site. The nucleotide-binding motifs coordinate the phosphates, the ribose and the base of a NTP molecule. The interaction between O2’ of the initiating NTP and Asp-306 stabilizes the ribose during the di-nucleotide synthesis. It is proposed that the first nucleotide binds to the elongation site, followed by binding to the initiation site of a second NTP, which will become the 5’-terminal nucleotide of the primer.

Miscellaneous. The bound zinc ion is not a cofactor. It is bound to a zinc knuckle motif that may be involved in sequence recognition and the binding of ssDNA.

Similarity. Belongs to the eukaryotic-type primase small subunit family.

RefSeq proteins (1): NP_000937* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002755	DNA_primase_S	Family
IPR014052	DNA_primase_ssu_euk/arc	Family

Pfam: PF01896

Enzyme classification (BRENDA):

• EC 2.7.7.102 — DNA primase AEP (BRENDA: 9 organisms, 25 substrates, 3 inhibitors, 8 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

5 substrates with measured Km, best-characterized 5. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
DNTP	5–198	3
5’-CTTCTTCTGTGC-3’	0.2	1
ATP	0.15	1
DATP	0.032	1
NTP	27.5	1

UniProt features (85 total): helix 23, binding site 18, mutagenesis site 18, strand 11, turn 5, active site 3, sequence variant 2, chain 1, region of interest 1, short sequence motif 1, modified residue 1, compositionally biased region 1

Structure

Experimental structures (PDB)

23 structures.

PDB	Method	Resolution (Å)
6RB4	X-RAY DIFFRACTION	1.5
4LIK	X-RAY DIFFRACTION	1.7
6R5E	X-RAY DIFFRACTION	1.85
6R5D	X-RAY DIFFRACTION	1.95
4MHQ	X-RAY DIFFRACTION	2.2
6R4U	X-RAY DIFFRACTION	2.2
6R4T	X-RAY DIFFRACTION	2.35
4LIL	X-RAY DIFFRACTION	2.6
4RR2	X-RAY DIFFRACTION	2.65
4BPU	X-RAY DIFFRACTION	2.7
6R4S	X-RAY DIFFRACTION	2.75
8VY3	ELECTRON MICROSCOPY	2.98
4BPW	X-RAY DIFFRACTION	3
8QJ7	ELECTRON MICROSCOPY	3.07
9C8V	ELECTRON MICROSCOPY	3.39
4BPX	X-RAY DIFFRACTION	3.4
8B9D	ELECTRON MICROSCOPY	3.4
8D0B	ELECTRON MICROSCOPY	3.43
8D9D	ELECTRON MICROSCOPY	3.59
5EXR	X-RAY DIFFRACTION	3.6
7OPL	ELECTRON MICROSCOPY	4.12
8D0K	ELECTRON MICROSCOPY	4.27
7U5C	ELECTRON MICROSCOPY	4.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49642-F1	92.79	0.84

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): 44; 109; 111

Ligand- & substrate-binding residues (18): 109; 109; 111; 111; 111; 111; 121; 122; 128; 131; 160–166; 306 …

Post-translational modifications (1): 1

Mutagenesis-validated functional residues (18):

Position	Phenotype
44	strongly decreases primase activity, which can be partially rescued by increasing primase concentration.
54	decreases primase activity.
56	loss of primase activity.
77	decreases primase activity.
109	loss of primase activity.
109	decreases the binding affinity for ntps.
111	loss of primase activity.
111	decreases the binding affinity for ntps.
114	slightly decreases primase activity.
116	slightly decreases primase activity.
160	abolishes ntp binding.
163	abolishes ntp binding.
166	abolishes ntp binding. loss of primase activity.
306	loss of primase activity.
306	decreases the binding affinity for ntps.
315	decreases the binding affinity for ntps. loss of primase activity.
318	decreases the binding affinity for ntps. loss of primase activity.
324	strongly decreases primase activity, which can be partially rescued by increasing primase concentration.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-113501	Inhibition of replication initiation of damaged DNA by RB1/E2F1
R-HSA-174411	Polymerase switching on the C-strand of the telomere
R-HSA-174430	Telomere C-strand synthesis initiation
R-HSA-68952	DNA replication initiation
R-HSA-68962	Activation of the pre-replicative complex
R-HSA-69091	Polymerase switching
R-HSA-69166	Removal of the Flap Intermediate
R-HSA-69183	Processive synthesis on the lagging strand
R-HSA-9710421	Defective pyroptosis

MSigDB gene sets: 483 (showing top): REACTOME_INHIBITION_OF_REPLICATION_INITIATION_OF_DAMAGED_DNA_BY_RB1_E2F1, REACTOME_DNA_REPLICATION, E2F_Q4_01, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GNF2_CENPF, PAL_PRMT5_TARGETS_UP, FISCHER_G1_S_CELL_CYCLE, FRASOR_RESPONSE_TO_SERM_OR_FULVESTRANT_DN, AACYNNNNTTCCS_UNKNOWN, KONG_E2F3_TARGETS, GNF2_RRM1, SHEPARD_BMYB_MORPHOLINO_DN, GOLDRATH_ANTIGEN_RESPONSE, AACWWCAANK_UNKNOWN, PATIL_LIVER_CANCER

GO Biological Process (4): DNA replication, synthesis of primer (GO:0006269), DNA replication initiation (GO:0006270), DNA replication (GO:0006260), DNA-templated DNA replication (GO:0006261)

GO Molecular Function (8): magnesium ion binding (GO:0000287), DNA-directed RNA polymerase activity (GO:0003899), zinc ion binding (GO:0008270), ribonucleotide binding (GO:0032553), protein binding (GO:0005515), transferase activity (GO:0016740), nucleotidyltransferase activity (GO:0016779), metal ion binding (GO:0046872)

GO Cellular Component (4): nucleoplasm (GO:0005654), alpha DNA polymerase:primase complex (GO:0005658), membrane (GO:0016020), DNA-directed RNA polymerase complex (GO:0000428)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Telomere C-strand (Lagging Strand) Synthesis	2
Lagging Strand Synthesis	2
E2F mediated regulation of DNA replication	1
Synthesis of DNA	1
DNA Replication Pre-Initiation	1
G1/S Transition	1
Leading Strand Synthesis	1
Processive synthesis on the lagging strand	1
Diseases of programmed cell death	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA-templated DNA replication	2
RNA biosynthetic process	2
DNA metabolic process	2
cellular anatomical structure	2
DNA biosynthetic process	1
DNA replication	1
metal ion binding	1
5’-3’ RNA polymerase activity	1
transition metal ion binding	1
nucleotide binding	1
carbohydrate derivative binding	1
binding	1
catalytic activity	1
transferase activity, transferring phosphorus-containing groups	1
cation binding	1
nuclear lumen	1
DNA polymerase complex	1
nuclear replisome	1
nuclear DNA-directed RNA polymerase complex	1
RNA polymerase complex	1

Protein interactions and networks

STRING

1966 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PRIM1	POLA2	Q14181	999
PRIM1	PRIM2	P49643	999
PRIM1	POLA1	P09884	987
PRIM1	POLD1	P28340	726
PRIM1	POLE	Q07864	670
PRIM1	CDC45	O75419	668
PRIM1	MCM10	Q7L590	666
PRIM1	POLE2	P56282	665
PRIM1	PRIMPOL	Q96LW4	654
PRIM1	MCM5	P33992	599
PRIM1	RFC4	P35249	590
PRIM1	CDC6	Q99741	572
PRIM1	POLD2	P49005	572
PRIM1	RFC2	P32846	565
PRIM1	MCM4	P33991	555
PRIM1	MCM6	Q14566	555

IntAct

99 interactions, top by confidence:

A	B	Type	Score
S100B	S100A4	psi-mi:“MI:0914”(association)	0.870
CDK8	MED19	psi-mi:“MI:2364”(proximity)	0.850
RFXANK	RFXAP	psi-mi:“MI:0914”(association)	0.780
BTF3L4	TXLNA	psi-mi:“MI:0914”(association)	0.780
PRIM1	PRIM2	psi-mi:“MI:0915”(physical association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
MMS19	ERCC2	psi-mi:“MI:0914”(association)	0.690
rep	POLA1	psi-mi:“MI:0914”(association)	0.670
PRIM1	POLA1	psi-mi:“MI:0914”(association)	0.640
QPRT	PIK3C2A	psi-mi:“MI:0914”(association)	0.640
POLA1	PRIM1	psi-mi:“MI:0914”(association)	0.640
HTT	PRIM1	psi-mi:“MI:0915”(physical association)	0.560
STN1	SMCO3	psi-mi:“MI:0914”(association)	0.530
LIPH	LRP5	psi-mi:“MI:0914”(association)	0.530
RNF31	GBP1	psi-mi:“MI:0914”(association)	0.530
rep	POLA1	psi-mi:“MI:0914”(association)	0.530
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
POLR3H	POLR3A	psi-mi:“MI:0914”(association)	0.530
BTF3L4	PRIM1	psi-mi:“MI:0914”(association)	0.530
PNMA2	CCDC85C	psi-mi:“MI:0914”(association)	0.530

BioGRID (145): PRIM1 (Affinity Capture-RNA), PRIM1 (Affinity Capture-RNA), PRIM1 (Affinity Capture-MS), PRIM1 (Affinity Capture-MS), PRIM1 (Affinity Capture-MS), PRIM1 (Affinity Capture-MS), PRIM1 (Affinity Capture-MS), PRIM1 (Co-fractionation), PRIM1 (Co-fractionation), PRIM1 (Co-fractionation), RPA2 (Co-fractionation), PRIM1 (Affinity Capture-MS), PRIM1 (Affinity Capture-MS), POLA2 (Affinity Capture-MS), PRIM2 (Affinity Capture-MS)

ESM2 similar proteins: A5DBC9, A8QHQ0, A8WZU5, A8XYX2, A8XYX3, B0W730, O14215, O74516, O74908, O80452, O81395, O94443, P09880, P10363, P20664, P34471, P35875, P49642, P51820, P90740, P91133, Q02792, Q04149, Q0JMY1, Q10313, Q11207, Q11208, Q17G65, Q24317, Q25998, Q28YQ7, Q2QRX6, Q45EK7, Q5RBG4, Q6CKI0, Q6CPQ8, Q6FYA6, Q7KQM1, Q7KRR5, Q84NP7

Diamond homologs: A0B688, A0RYW9, A1RRN3, A2BN97, A2ST15, A3DM85, A3MUU9, A4WLS1, A5UJA2, A7I9Q9, B0R5P1, B1YAF6, B6YV39, B8GGQ0, C3MPG7, C3MYF5, C3N549, C3NDP7, C3NI04, C4KGQ2, O26685, O29516, P20664, P49642, Q12W69, Q2FPD1, Q2NI23, Q3IP66, Q4J9B0, Q58249, Q5JJ72, Q8TXS4, Q8ZTY1, Q973F6, Q979L5, Q97Z83, Q9HJJ2, Q9HPU3, Q9V292, Q9YEZ8

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
clofarabine	“down-regulates activity”	PRIM1	“chemical inhibition”
PRIM1	“form complex”	“DNA primase complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 111 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
Innate Immune System	12	3.9×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	36
Likely benign	7
Benign	1

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
981920	NM_000946.3(PRIM1):c.638+36C>G	Pathogenic
981921	NM_000946.3(PRIM1):c.103+1G>T	Pathogenic
981922	NM_000946.3(PRIM1):c.901T>C (p.Cys301Arg)	Pathogenic

SpliceAI

1753 predictions. Top by Δscore:

Variant	Effect	Δscore
12:56734146:CCA:C	donor_gain	1.0000
12:56734146:CCACT:C	donor_gain	1.0000
12:56734242:TAAT:T	acceptor_gain	1.0000
12:56734244:AT:A	acceptor_gain	1.0000
12:56734244:ATC:A	acceptor_loss	1.0000
12:56734246:C:CC	acceptor_gain	1.0000
12:56734246:CTAA:C	acceptor_loss	1.0000
12:56734247:T:A	acceptor_loss	1.0000
12:56738428:CCTTA:C	donor_gain	1.0000
12:56738429:CTTA:C	donor_loss	1.0000
12:56738431:TACCT:T	donor_loss	1.0000
12:56738432:A:AC	donor_gain	1.0000
12:56738433:C:CC	donor_gain	1.0000
12:56738433:CCT:C	donor_gain	1.0000
12:56738521:TGAAG:T	acceptor_gain	1.0000
12:56738522:GAAG:G	acceptor_gain	1.0000
12:56738523:AAG:A	acceptor_gain	1.0000
12:56738524:AG:A	acceptor_gain	1.0000
12:56738524:AGCT:A	acceptor_loss	1.0000
12:56738525:GCTG:G	acceptor_loss	1.0000
12:56738526:C:CC	acceptor_gain	1.0000
12:56738526:CTG:C	acceptor_loss	1.0000
12:56738527:T:A	acceptor_loss	1.0000
12:56738529:CAAG:C	acceptor_gain	1.0000
12:56738530:A:T	acceptor_gain	1.0000
12:56738532:G:C	acceptor_gain	1.0000
12:56738532:G:GC	acceptor_gain	1.0000
12:56738536:C:CT	acceptor_gain	1.0000
12:56738537:A:T	acceptor_gain	1.0000
12:56739289:CATA:C	donor_loss	1.0000

AlphaMissense

2831 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:56739360:C:G	R329P	1.000
12:56741445:A:C	H324Q	1.000
12:56741445:A:T	H324Q	1.000
12:56741446:T:C	H324R	1.000
12:56741447:G:C	H324D	1.000
12:56741449:A:T	V323D	1.000
12:56741451:A:C	S322R	1.000
12:56741451:A:T	S322R	1.000
12:56741453:T:G	S322R	1.000
12:56741460:G:C	S319R	1.000
12:56741460:G:T	S319R	1.000
12:56741462:T:G	S319R	1.000
12:56741463:C:A	K318N	1.000
12:56741463:C:G	K318N	1.000
12:56741465:T:C	K318E	1.000
12:56741467:A:G	L317P	1.000
12:56741467:A:T	L317Q	1.000
12:56741470:A:G	L316P	1.000
12:56741470:A:T	L316Q	1.000
12:56741472:A:C	H315Q	1.000
12:56741472:A:T	H315Q	1.000
12:56741473:T:C	H315R	1.000
12:56741473:T:G	H315P	1.000
12:56741474:G:C	H315D	1.000
12:56741474:G:T	H315N	1.000
12:56741487:G:C	S310R	1.000
12:56741487:G:T	S310R	1.000
12:56741489:T:G	S310R	1.000
12:56741491:A:G	V309A	1.000
12:56741491:A:T	V309D	1.000

dbSNP variants (sampled 300 via entrez): RS1000114124 (12:56748559 G>A), RS1000194776 (12:56737639 G>A,C), RS1000203005 (12:56737967 T>C,G), RS1000392825 (12:56752393 G>A), RS1000778054 (12:56754079 G>A,C), RS1000788948 (12:56745063 C>T), RS1001036950 (12:56731929 C>A), RS1001294213 (12:56738212 G>C,T), RS1001509791 (12:56744376 C>G), RS1001525361 (12:56752845 TTTTTTTTA>T,TTTTTTTTATTTTTTTA), RS1001605904 (12:56752030 C>A), RS1001664948 (12:56751708 G>C), RS1001892681 (12:56746504 G>A), RS1001939115 (12:56753274 T>C), RS1002011732 (12:56753049 C>A,T)

Disease associations

OMIM: gene MIM:176635 | disease phenotypes: MIM:210600, MIM:620005

GenCC curated gene-disease

Disease	Classification	Inheritance
primordial dwarfism-immunodeficiency-lipodystrophy syndrome	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
primordial dwarfism-immunodeficiency-lipodystrophy syndrome	Moderate	AR

Mondo (3): primary ovarian failure (MONDO:0005387), Seckel syndrome (MONDO:0019342), primordial dwarfism-immunodeficiency-lipodystrophy syndrome (MONDO:0859276)

Orphanet (3): Microcephalic primordial dwarfism (Orphanet:324761), Seckel syndrome (Orphanet:808), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

58 total (30 of 58 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000089	Renal hypoplasia
HP:0000252	Microcephaly
HP:0000270	Delayed cranial suture closure
HP:0000319	Smooth philtrum
HP:0000337	Broad forehead
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000437	Depressed nasal tip
HP:0000518	Cataract
HP:0000568	Microphthalmia
HP:0000581	Blepharophimosis
HP:0000691	Microdontia
HP:0000821	Hypothyroidism
HP:0000878	11 pairs of ribs
HP:0001182	Tapered finger
HP:0001363	Craniosynostosis
HP:0001385	Hip dysplasia
HP:0001395	Hepatic fibrosis
HP:0001409	Portal hypertension
HP:0001511	Intrauterine growth retardation
HP:0001631	Atrial septal defect
HP:0001643	Patent ductus arteriosus
HP:0001655	Patent foramen ovale
HP:0001738	Exocrine pancreatic insufficiency
HP:0001747	Accessory spleen
HP:0001873	Thrombocytopenia
HP:0001888	Decreased total lymphocyte count
HP:0001903	Anemia

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST001381_1	Menopause (age at onset)	2.000000e-19
GCST004602_159	Mean corpuscular volume	1.000000e-09
GCST004607_48	Plateletcrit	1.000000e-10
GCST005312_1	Menopause (age at onset)	2.000000e-19
GCST005996_51	Red blood cell count	1.000000e-09
GCST008839_250	Height	7.000000e-14
GCST008916_110	Asthma	1.000000e-27
GCST008916_18	Asthma	8.000000e-18
GCST90000025_972	Appendicular lean mass	2.000000e-30
GCST90000026_37	Appendicular lean mass	7.000000e-15
GCST90000027_17	Appendicular lean mass	5.000000e-18
GCST90002390_65	Mean corpuscular hemoglobin	2.000000e-24
GCST90002392_386	Mean corpuscular volume	2.000000e-29
GCST90002393_417	Monocyte count	6.000000e-11
GCST90002396_529	Mean reticulocyte volume	7.000000e-17
GCST90002397_206	Mean spheric corpuscular volume	5.000000e-21
GCST90002400_92	Plateletcrit	6.000000e-11

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause
EFO:0007985	platelet crit
EFO:0004305	erythrocyte count
EFO:0004980	appendicular lean mass
EFO:0004527	mean corpuscular hemoglobin
EFO:0005091	monocyte count
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2363042 (PROTEIN FAMILY)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, increases expression	3
Estradiol	increases expression	3
Cyclosporine	increases expression, decreases expression	3
sodium arsenite	decreases expression	2
Resveratrol	affects cotreatment, increases expression, decreases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Air Pollutants, Occupational	decreases expression, increases abundance, increases expression, affects expression	2
Benzo(a)pyrene	decreases expression	2
Silicon Dioxide	increases expression, decreases expression	2
GSK-J4	decreases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
kojic acid	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
phenethyl isothiocyanate	decreases expression	1
corosolic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1
K 7174	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
palbociclib	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	PHASE1/PHASE2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	PHASE1/PHASE2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	PHASE1/PHASE2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	PHASE1/PHASE2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	PHASE1/PHASE2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF
NCT03069209	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Premature Ovarian Failure (POF)
NCT03985462	PHASE1/PHASE2	WITHDRAWN	Very Small Embryonic-like Stem Cells for Ovary
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT04071574	PHASE1/PHASE2	COMPLETED	Comparative Study on the Efficacy of Ovarian Stimulation Protocols on the Success Rate of ICSI in Female Infertility
NCT04922398	PHASE1/PHASE2	UNKNOWN	Ovarian Injection of PRP (Platelet -Rich Plasma) Vs Normal Saline in Premature Ovarian Insufficiency
NCT05462379	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Autologous Heterotopic Fresh Ovarian Graft in Woman With LACC Eligible for Pelvic Radiotherapy Treatment.
NCT06202547	PHASE1/PHASE2	UNKNOWN	Intra-ovarian Injection of MSC-EVs in Idiopathic Premature Ovarian Failure
NCT01129947	EARLY_PHASE1	WITHDRAWN	The Use of DHEA in Women With Premature Ovarian Failure
NCT05522634	EARLY_PHASE1	UNKNOWN	A Clinical Study of Chinese Herbal Compound TJAOA101 in the Treatment of Premature Ovarian Insufficiency
NCT07308327	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	The Influence of Gut Microbiota on Ovarian Function: A Single-center, Randomized,Double Blind, Parallel-controlled, Exploratory Clinical Trial
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00001306	Not specified	COMPLETED	Steroid Therapy in Autoimmune Premature Ovarian Failure
NCT00006156	Not specified	COMPLETED	Feasibility Study for Development of an Early Test for Ovarian Failure
NCT00119925	Not specified	UNKNOWN	‘SPRING’-Study: Subfertility Guidelines: Patient Related Implementation in the Netherlands Among Gynaecologists