RAD51D

Summary

RAD51D (RAD51 paralog D, HGNC:9823) is a protein-coding gene on chromosome 17q12, encoding DNA repair protein RAD51 homolog 4 (O75771). Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA breaks arising during DNA replication or induced by DNA-damaging agents. In precision oncology, RAD51D Mutation confers sensitivity to Olaparib in Castration-resistant Prostate Carcinoma (CIViC Level A). It is a selective cancer dependency (DepMap: 74.9% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51, which are known to be involved in the homologous recombination and repair of DNA. This protein forms a complex with several other members of the RAD51 family, including RAD51L1, RAD51L2, and XRCC2. The protein complex formed with this protein has been shown to catalyze homologous pairing between single- and double-stranded DNA, and is thought to play a role in the early stage of recombinational repair of DNA. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream ring finger and FYVE-like domain containing 1 (RFFL) gene.

Source: NCBI Gene 5892 — RefSeq curated summary.

At a glance

• Gene–disease (curated): RAD51D-related cancer predisposition (Definitive, ClinGen) — +2 more curated relationships
• Clinical variants (ClinVar): 1,223 total — 98 pathogenic, 58 likely-pathogenic
• Phenotypes (HPO): 7
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Cancer dependency (DepMap): dependent in 74.9% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_002878

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9823
Approved symbol	RAD51D
Name	RAD51 paralog D
Location	17q12
Locus type	gene with protein product
Status	Approved
Aliases	R51H3, Trad, HsTRAD
Ensembl gene	ENSG00000185379
Ensembl biotype	protein_coding
OMIM	602954
Entrez	5892

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 15 protein_coding, 7 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined, 4 retained_intron

ENST00000335858, ENST00000345365, ENST00000394589, ENST00000415064, ENST00000460118, ENST00000585343, ENST00000585947, ENST00000585982, ENST00000586044, ENST00000586186, ENST00000586210, ENST00000587405, ENST00000587977, ENST00000587982, ENST00000588372, ENST00000588594, ENST00000589506, ENST00000590016, ENST00000590631, ENST00000592430, ENST00000592577, ENST00000592850, ENST00000592928, ENST00000851373, ENST00000928068, ENST00000928069, ENST00000928070, ENST00000928071, ENST00000928072, ENST00000960682

RefSeq mRNA: 3 — MANE Select: NM_002878 NM_001142571, NM_002878, NM_133629

CCDS: CCDS11287, CCDS11288, CCDS45646

Canonical transcript exons

ENST00000345365 — 10 exons

Exon	Start	End
ENSE00001391423	35092221	35101036
ENSE00001420136	35119532	35119860
ENSE00003587034	35106988	35107122
ENSE00003609711	35103254	35103324
ENSE00003639346	35106386	35106481
ENSE00003646368	35119111	35119172
ENSE00003650430	35103454	35103544
ENSE00003657664	35107366	35107447
ENSE00003667677	35101201	35101365
ENSE00003713562	35118501	35118619

Expression profiles

Bgee: expression breadth ubiquitous, 187 present calls, max score 95.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.5946 / max 61.1785, expressed in 1599 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
165340	1.9465	1101
165339	1.6302	1138
165341	0.0098	3
165342	0.0081	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	95.93	gold quality
male germ cell	CL:0000015	92.39	gold quality
oocyte	CL:0000023	85.00	silver quality
right testis	UBERON:0004534	84.95	gold quality
left testis	UBERON:0004533	84.52	gold quality
cortical plate	UBERON:0005343	82.04	gold quality
testis	UBERON:0000473	81.88	gold quality
stromal cell of endometrium	CL:0002255	81.52	gold quality
ganglionic eminence	UBERON:0004023	81.44	gold quality
prefrontal cortex	UBERON:0000451	81.16	gold quality
colonic epithelium	UBERON:0000397	81.05	gold quality
right frontal lobe	UBERON:0002810	81.02	gold quality
granulocyte	CL:0000094	80.10	gold quality
endothelial cell	CL:0000115	79.91	gold quality
ventricular zone	UBERON:0003053	79.88	gold quality
cingulate cortex	UBERON:0003027	79.01	gold quality
anterior cingulate cortex	UBERON:0009835	78.81	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	78.80	gold quality
body of uterus	UBERON:0009853	78.74	gold quality
left ovary	UBERON:0002119	78.37	gold quality
Brodmann (1909) area 9	UBERON:0013540	78.31	gold quality
thoracic aorta	UBERON:0001515	78.30	gold quality
apex of heart	UBERON:0002098	78.29	gold quality
ascending aorta	UBERON:0001496	78.27	gold quality
popliteal artery	UBERON:0002250	78.06	gold quality
tibial artery	UBERON:0007610	78.05	gold quality
aorta	UBERON:0000947	78.03	gold quality
right ovary	UBERON:0002118	78.00	gold quality
right lobe of thyroid gland	UBERON:0001119	77.92	gold quality
left coronary artery	UBERON:0001626	77.90	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-MTAB-7249	no	19.05
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

62 targeting RAD51D, 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-4776-3P	100.00	68.73	1340
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-892A	99.54	68.16	1141
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4770	99.49	69.09	1451
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-6083	99.47	68.73	2393
HSA-MIR-4318	99.38	66.94	1505
HSA-MIR-4652-3P	99.33	70.02	2742

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 74.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Homologous pairing and ring and filament structure formation activities of the human Xrcc2*Rad51D complex (PMID:11834724)
• RAD51L3 cooperates with Bloom Syndrome Protein during the late stages of homologous recombination processes that serve to restore productive DNA replication at sites of damaged or stalled replication forks (PMID:12975363)
• Telomere maintenance requires RAD51D. (PMID:15109494)
• E233G single nucleotide polymorphism is a low-penetrance susceptibility gene in the specific subgroup of high-risk familial breast cancer cases that are not related to BRCA1/2. (PMID:15170666)
• Interactions between RAD51D and its XRCC2 and RAD51C partners require a functional RAD51D Walker B ATPase motif, but not motif A. (PMID:16717288)
• The RAD51D E233G variant is not associated with breast cancer. (PMID:18058226)
• Polymorphisms in RAD51D gene is associated with breast cancer. (PMID:20054644)
• The N-terminal domain of Rad51D is required for the ssDNA-specific binding function of human Rad51D. (PMID:21111057)
• These data indicate that RAD51D mutation testing may have clinical utility in individuals with ovarian cancer and their families. (PMID:21822267)
• The RAD51D should be included in genetic screening of ovarian cancer families that do not have BRCA1/BRCA2 mutations. (PMID:22415235)
• RAD51D is primarily a moderate penetrance susceptibility gene for ovarian cancer, with clinical significance for the carriers. (PMID:22652533)
• the contribution of RAD51C and RAD51D gene mutations to an inherited high risk of ovarian cancer is very small (PMID:22752287)
• loss-of-function mutations in RAD51D predispose to ovarian carcinoma but not to breast carcinoma. (PMID:22986143)
• Our data provide additional evidence that RAD51D mutations are enriched among ovarian cancer patients, but are extremely rare among familial breast cancer patients. (PMID:23372765)
• endogenous regulation of RAD51D by miR-103/107 was observed in several tumor subtypes; both miR-103 and miR-107 directly target and regulate RAD51 and RAD51D (PMID:24088786)
• We aimed to determine the prevalence of germline RAD51D mutations in Spanish breast and ovarian cancer families negative for BRCA1/BRCA2 (PMID:24130102)
• a mutation analysis in 171 high-risk BRCA1 and BRCA2 negative ovarian cancer patients, to evaluate the frequency of hereditary RAD51C and RAD51D variants in Czech population, is reported. (PMID:26057125)
• RAD51C and RAD51D are moderate ovarian cancer susceptibility genes. (PMID:26261251)
• of Rad51d mediated by E3 Ligase Rnf138 has a role in the homologous recombination repair pathway (PMID:27195665)
• variants in RAD51D were associated with moderate risks of breast cancer. (PMID:28418444)
• Results highlight the importance of a functional RAD51D-XRCC2 interaction to promote HR and prevent the development of HGSC. (PMID:28646019)
• results increase our knowledge about the RAD51C and RAD51D mutation spectrum and support the notion that these genes should be included in the gene panel testing performed on patients with hereditary breast and ovarian cancer syndrome (PMID:29409816)
• Our results validate the integration of PALB2, RAD51C, and RAD51D in the diagnosis of hereditary breast and ovarian cancer and suggest that the other genes are involved in an oligogenic determinism. (PMID:29988077)
• Contribution of RAD51D germline mutations in breast and ovarian cancer in Greece. (PMID:30111881)
• RAD51D germline mutations is associated with breast cancer. (PMID:30165555)
• Association between polymorphisms in MicroRNA target sites of RAD51D genes and risk of hepatocellular carcinoma. (PMID:30883040)
• Ovarian and Breast Cancer Risks Associated With Pathogenic Variants in RAD51C and RAD51D. (PMID:32107557)
• BRIP1, RAD51C, and RAD51D mutations are associated with high susceptibility to ovarian cancer: mutation prevalence and precise risk estimates based on a pooled analysis of ~30,000 cases. (PMID:32359370)
• New germline mutations in non-BRCA genes among breast cancer women of Mongoloid origin. (PMID:32601921)
• Sequential role of RAD51 paralog complexes in replication fork remodeling and restart. (PMID:32669601)
• The RAD51D c.82G>A (p.Val28Met) variant disrupts normal splicing and is associated with hereditary ovarian cancer. (PMID:33452952)
• Germline mutations in RAD51C and RAD51D and hereditary predisposition to ovarian cancer. (PMID:33657816)
• A decade of RAD51C and RAD51D germline variants in cancer. (PMID:34923718)
• Identification of new RAD51D-regulating microRNAs that also emerge as potent inhibitors of the Fanconi anemia/homologous recombination pathways. (PMID:35904444)
• Enhancing the BOADICEA cancer risk prediction model to incorporate new data on RAD51C, RAD51D, BARD1 updates to tumour pathology and cancer incidence. (PMID:36162851)
• YTHDF3 mediates HNF1alpha regulation of cervical cancer radio-resistance by promoting RAD51D translation in an m6A-dependent manner. (PMID:36380687)
• UK consensus recommendations for clinical management of cancer risk for women with germline pathogenic variants in cancer predisposition genes: RAD51C, RAD51D, BRIP1 and PALB2. (PMID:36411032)
• Clinical characteristics and survival analysis of Chinese ovarian cancer patients with RAD51D germline mutations. (PMID:36544182)
• Structure and function of the RAD51B-RAD51C-RAD51D-XRCC2 tumour suppressor. (PMID:37344587)
• Structural insights into BCDX2 complex function in homologous recombination. (PMID:37344589)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rad51d	ENSDARG00000026400
mus_musculus	Rad51d	ENSMUSG00000018841
caenorhabditis_elegans		WBGENE00004342

Paralogs (6): RAD51 (ENSG00000051180), DMC1 (ENSG00000100206), RAD51C (ENSG00000108384), XRCC3 (ENSG00000126215), RAD51B (ENSG00000182185), XRCC2 (ENSG00000196584)

Protein

Protein identifiers

DNA repair protein RAD51 homolog 4 — O75771 (reviewed: O75771)

Alternative names: R51H3, RAD51 homolog D, RAD51-like protein 3, TRAD

All UniProt accessions (7): O75771, H0UID0, K7EKG7, K7ERM7, K7ESI1, K7ESL4, Q7Z790

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA breaks arising during DNA replication or induced by DNA-damaging agents. Bind to single-stranded DNA (ssDNA) and has DNA-dependent ATPase activity. Part of the RAD51 paralog protein complex BCDX2 which acts in the BRCA1-BRCA2-dependent HR pathway. Upon DNA damage, BCDX2 acts downstream of BRCA2 recruitment and upstream of RAD51 recruitment. BCDX2 binds predominantly to the intersection of the four duplex arms of the Holliday junction and to junction of replication forks. The BCDX2 complex was originally reported to bind single-stranded DNA, single-stranded gaps in duplex DNA and specifically to nicks in duplex DNA. Involved in telomere maintenance. The BCDX2 subcomplex XRCC2:RAD51D can stimulate Holliday junction resolution by BLM.

Subunit / interactions. Part of the BCDX2 complex consisting of RAD51B, RAD51C, RAD51D and XRCC2; the complex has a ring-like structure arranged into a flat disc around a central channel. In the absence of DNA, the BCDX2 subcomplex XRCC2:RAD51D formed a multimeric ring structure; in the presence of single-stranded DNA it formed a filamentous structure with the ssDNA. Interacts with SWSAP1 and ZSWIM7; involved in homologous recombination repair. Interacts with BLM; required for stimulation of BLM activity by the BCDX2 subcomplex XRCC2:RAD51D.

Subcellular location. Nucleus. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Chromosome. Telomere.

Tissue specificity. Expressed in colon, prostate, spleen, testis, ovary, thymus and small intestine. Weakly expressed in leukocytes.

Disease relevance. Breast-ovarian cancer, familial, 4 (BROVCA4) [MIM:614291] A condition associated with familial predisposition to cancer of the breast and ovaries. Characteristic features in affected families are an early age of onset of breast cancer (often before age 50), increased chance of bilateral cancers (cancer that develop in both breasts, or both ovaries, independently), frequent occurrence of breast cancer among men, increased incidence of tumors of other specific organs, such as the prostate. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the RecA family. RAD51 subfamily.

Isoforms (8)

UniProt ID	Names	Canonical?
O75771-1	1, TRAD	yes
O75771-2	2, TRAD-D1, D2
O75771-3	3, TRAD-D3
O75771-4	4, TRAD-D4
O75771-5	5, TRAD-D5
O75771-6	6, TRAD-D6, D7
O75771-7	7, TRAD-D8
O75771-8	8

RefSeq proteins (3): NP_001136043, NP_002869, NP_598332 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003593	AAA+_ATPase	Domain
IPR013632	Rad51_C	Domain
IPR016467	DNA_recomb/repair_RecA-like	Family
IPR020588	RecA_ATP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR047323	Rad51D_C	Domain
IPR048943	RAD51D_N	Domain
IPR051988	HRR_RAD51_Paralog	Family

Pfam: PF08423, PF21794

UniProt features (51 total): helix 14, strand 14, splice variant 10, sequence variant 6, turn 3, chain 1, region of interest 1, sequence conflict 1, binding site 1

Structure

Experimental structures (PDB)

17 structures.

PDB	Method	Resolution (Å)
8OUZ	ELECTRON MICROSCOPY	2.2
8FAZ	ELECTRON MICROSCOPY	2.3
9SVY	ELECTRON MICROSCOPY	2.6
9Q29	ELECTRON MICROSCOPY	2.61
9Q2A	ELECTRON MICROSCOPY	2.67
9SVX	ELECTRON MICROSCOPY	2.7
9Q23	ELECTRON MICROSCOPY	2.84
9Q28	ELECTRON MICROSCOPY	2.84
9ZZR	ELECTRON MICROSCOPY	2.95
9SW0	ELECTRON MICROSCOPY	3
8GBJ	ELECTRON MICROSCOPY	3.11
9ON2	ELECTRON MICROSCOPY	3.16
9Q2B	ELECTRON MICROSCOPY	3.2
9Q25	ELECTRON MICROSCOPY	3.24
8OUY	ELECTRON MICROSCOPY	3.4
9OMZ	ELECTRON MICROSCOPY	3.51
2KZ3	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75771-F1	88.64	0.71

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 (1): 107–114

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-5685942	HDR through Homologous Recombination (HRR)
R-HSA-5693554	Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)
R-HSA-5693568	Resolution of D-loop Structures through Holliday Junction Intermediates
R-HSA-5693579	Homologous DNA Pairing and Strand Exchange
R-HSA-5693616	Presynaptic phase of homologous DNA pairing and strand exchange
R-HSA-6796648	TP53 Regulates Transcription of DNA Repair Genes
R-HSA-9701192	Defective homologous recombination repair (HRR) due to BRCA1 loss of function
R-HSA-9704331	Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function
R-HSA-9704646	Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function
R-HSA-9709603	Impaired BRCA2 binding to PALB2

MSigDB gene sets: 246 (showing top): MORF_ITGA2, GOBP_CHROMOSOME_ORGANIZATION, MORF_MSH3, XU_HGF_TARGETS_REPRESSED_BY_AKT1_DN, MODULE_45, MORF_BRCA1, GOBP_TELOMERE_ORGANIZATION, KAUFFMANN_DNA_REPAIR_GENES, AATGGAG_MIR136, CAGCTG_AP4_Q5, KEGG_HOMOLOGOUS_RECOMBINATION, MORF_RAD51L3, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_ORGANELLE_FISSION, DOANE_RESPONSE_TO_ANDROGEN_DN

GO Biological Process (11): telomere maintenance via recombination (GO:0000722), telomere maintenance (GO:0000723), double-strand break repair via homologous recombination (GO:0000724), DNA repair (GO:0006281), reciprocal meiotic recombination (GO:0007131), interstrand cross-link repair (GO:0036297), DNA strand invasion (GO:0042148), regulation of cell cycle (GO:0051726), DNA recombination (GO:0006310), DNA damage response (GO:0006974), chromosome organization (GO:0051276)

GO Molecular Function (10): DNA binding (GO:0003677), single-stranded DNA binding (GO:0003697), ATP binding (GO:0005524), ATP-dependent activity, acting on DNA (GO:0008094), gamma-tubulin binding (GO:0043015), ATP-dependent DNA damage sensor activity (GO:0140664), nucleotide binding (GO:0000166), four-way junction DNA binding (GO:0000400), protein binding (GO:0005515), ATP hydrolysis activity (GO:0016887)

GO Cellular Component (10): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), nucleoplasm (GO:0005654), replication fork (GO:0005657), centrosome (GO:0005813), microtubule organizing center (GO:0005815), Rad51B-Rad51C-Rad51D-XRCC2 complex (GO:0033063), chromosome (GO:0005694), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Resolution of D-Loop Structures	2
Defective homologous recombination repair (HRR) due to PALB2 loss of function	2
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1
HDR through Homologous Recombination (HRR)	1
Homologous DNA Pairing and Strand Exchange	1
Transcriptional Regulation by TP53	1
Diseases of DNA Double-Strand Break Repair	1
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	4
cellular anatomical structure	4
ATP-dependent activity	2
intracellular membraneless organelle	2
telomere maintenance	1
mitotic recombination	1
telomere organization	1
recombinational repair	1
double-strand break repair	1
DNA damage response	1
meiosis I	1
reciprocal homologous recombination	1
meiotic cell cycle process	1
DNA repair	1
DNA recombination	1
cell cycle	1
regulation of cellular process	1
cellular response to stress	1
organelle organization	1
nucleic acid binding	1
DNA binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ATP hydrolysis activity	1
catalytic activity, acting on DNA	1
tubulin binding	1
ATP-dependent activity, acting on DNA	1
DNA damage sensor activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
DNA secondary structure binding	1
binding	1
ribonucleoside triphosphate phosphatase activity	1
chromosomal region	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
chromosome	1
centriole	1
microtubule organizing center	1
microtubule cytoskeleton	1

Protein interactions and networks

STRING

2644 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAD51D	XRCC2	O43543	999
RAD51D	RAD51C	O43502	992
RAD51D	RAD51B	O15315	991
RAD51D	BRCA2	P51587	938
RAD51D	BRCA1	P38398	904
RAD51D	PALB2	Q86YC2	897
RAD51D	BARD1	Q99728	885
RAD51D	FANCM	Q8IYD8	845
RAD51D	MLH1	P40692	838
RAD51D	CHEK2	O96017	833
RAD51D	ATM	Q13315	831
RAD51D	MSH6	P52701	814
RAD51D	MRE11	P49959	808
RAD51D	RAD54L	Q92698	795
RAD51D	MSH2	P43246	793

IntAct

256 interactions, top by confidence:

A	B	Type	Score
RAD51D	XRCC2	psi-mi:“MI:0915”(physical association)	0.980
XRCC2	RAD51D	psi-mi:“MI:0915”(physical association)	0.980
IKZF3	RAD51D	psi-mi:“MI:0915”(physical association)	0.850
RAD51D	IKZF3	psi-mi:“MI:0915”(physical association)	0.850
RAD51D	AMOTL2	psi-mi:“MI:0915”(physical association)	0.830
AMOTL2	RAD51D	psi-mi:“MI:0915”(physical association)	0.830

BioGRID (189): RAD51D (Two-hybrid), RAD51D (Two-hybrid), XRCC2 (Two-hybrid), IKZF1 (Two-hybrid), IKZF3 (Two-hybrid), AMOTL2 (Two-hybrid), PRDM14 (Two-hybrid), LZTS2 (Two-hybrid), LNX1 (Two-hybrid), C1orf94 (Two-hybrid), CEP57L1 (Two-hybrid), RAD51D (Affinity Capture-RNA), RAD51D (Affinity Capture-RNA), RAD51D (Affinity Capture-MS), RAD51D (Affinity Capture-MS)

ESM2 similar proteins: A1L1C2, A3KNW0, A6H603, A6NFQ2, A6QLU7, A9ULG4, B1H1N7, E1BE10, E2RD63, O35405, O55230, O60294, O60906, O75771, O95479, P21709, P51839, P56201, Q0V8L6, Q149M9, Q1JPJ9, Q28DT3, Q2KJJ8, Q2TBP8, Q4R583, Q5FVH2, Q5R4Y7, Q5XIA3, Q60750, Q643R3, Q6NVG1, Q6QHF9, Q80XS7, Q865R1, Q8BG07, Q8BYR1, Q8C0L6, Q8CFX1, Q8IV08, Q8N0W3

Diamond homologs: A3CXI2, A3MXX9, A4FYL0, A4WN87, A4YCN4, A5UKT8, A5UMW0, A6VJS2, A8AB83, B0R636, B1YC14, B6YXT4, B8BM09, B8D610, C3MRI1, C3MY77, C3MZK6, C3N7M8, C3NFU5, C4KIT6, C5A2F7, C6A0N1, O27728, O28184, O29269, O35719, O55230, O57859, O74036, O75771, O93748, P0CW60, P0CW61, P0CW91, P0CW92, P25453, P25454, P36601, P37384, P50265

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RNF138	“down-regulates quantity by destabilization”	RAD51D	ubiquitination

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

1223 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	98
Likely pathogenic	58
Uncertain significance	511
Likely benign	267
Benign	43

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1072692	NC_000017.10:g.(?33446541)(33446632_?)del	Pathogenic
1072693	NC_000017.10:g.(?33443985)(33446632_?)del	Pathogenic
1072694	NC_000017.10:g.(?33427972)(33430573_?)del	Pathogenic
1074165	NM_002878.4(RAD51D):c.167dup (p.Leu57fs)	Pathogenic
1074527	NM_002878.4(RAD51D):c.502C>T (p.Gln168Ter)	Pathogenic
1075870	NM_002878.4(RAD51D):c.256del (p.Ile86fs)	Pathogenic
1098875	NM_002878.4(RAD51D):c.754del (p.Thr252fs)	Pathogenic
1098883	NM_002878.4(RAD51D):c.24_27del (p.Cys9fs)	Pathogenic
1177652	NM_002878.4:c.82_577-1del	Pathogenic
1177657	NM_002878.4:c.1_263del	Pathogenic
1177659	NM_002878.4(RAD51D):c.146_263+1del	Pathogenic
1177660	NM_002878.4:c.740_987del	Pathogenic
1177662	NM_001142571.1:c.963_1047del	Pathogenic
1177663	NM_002878.4:c.1_987del	Pathogenic
141143	NM_002878.4(RAD51D):c.649_655delinsTGAGGTT (p.Gly217_Gln219delinsTer)	Pathogenic
142811	NM_002878.4(RAD51D):c.140_141insAA (p.Tyr47Ter)	Pathogenic
1453810	NM_002878.4(RAD51D):c.482dup (p.Glu162fs)	Pathogenic
1458065	NM_002878.4(RAD51D):c.486del (p.Ala163fs)	Pathogenic
1472197	NM_002878.4(RAD51D):c.576+2T>C	Pathogenic
1713232	NM_002878.4(RAD51D):c.896_*505del597insT (p.Ser299fs)	Pathogenic
1735332	NM_002878.4(RAD51D):c.382del (p.Leu128fs)	Pathogenic
1739847	NM_002878.4(RAD51D):c.433del (p.Arg145fs)	Pathogenic
1749751	NM_002878.4(RAD51D):c.57dup (p.Leu20fs)	Pathogenic
1756210	NM_002878.4(RAD51D):c.693_694delinsTT (p.Arg232Ter)	Pathogenic
1756261	NM_002878.4(RAD51D):c.694_715delinsTGAGAGCTGAAGACCCTGGCCT (p.Arg232_Arg239delinsTer)	Pathogenic
1795803	NM_002878.4(RAD51D):c.277_280del (p.Leu93fs)	Pathogenic
1798902	NM_002878.4(RAD51D):c.301G>T (p.Glu101Ter)	Pathogenic
1801549	NM_002878.4(RAD51D):c.941G>A (p.Trp314Ter)	Pathogenic
1801550	NM_002878.4(RAD51D):c.263+1617C>T	Pathogenic
1801650	NM_002878.4(RAD51D):c.974del (p.Gly325fs)	Pathogenic

SpliceAI

1943 predictions. Top by Δscore:

Variant	Effect	Δscore
17:35101196:CTCA:C	donor_loss	1.0000
17:35101197:TCA:T	donor_loss	1.0000
17:35101198:CA:C	donor_loss	1.0000
17:35101198:CACCT:C	donor_loss	1.0000
17:35101200:C:CT	donor_loss	1.0000
17:35103215:A:C	donor_gain	1.0000
17:35103247:T:TA	donor_gain	1.0000
17:35106382:TCA:T	donor_loss	1.0000
17:35106382:TCACC:T	donor_loss	1.0000
17:35106383:CA:C	donor_loss	1.0000
17:35106384:A:C	donor_loss	1.0000
17:35106385:C:CT	donor_loss	1.0000
17:35106385:CCTG:C	donor_gain	1.0000
17:35106478:CTGC:C	acceptor_gain	1.0000
17:35106482:C:CC	acceptor_gain	1.0000
17:35106482:CTGA:C	acceptor_loss	1.0000
17:35106483:T:G	acceptor_loss	1.0000
17:35106488:C:CT	acceptor_gain	1.0000
17:35106488:CGG:C	acceptor_gain	1.0000
17:35106489:G:T	acceptor_gain	1.0000
17:35106490:G:C	acceptor_gain	1.0000
17:35106490:G:GC	acceptor_gain	1.0000
17:35121289:ACCAT:A	donor_gain	1.0000
17:35121290:CCATC:C	donor_gain	1.0000
17:35101195:GCTCA:G	donor_loss	0.9900
17:35101366:C:A	acceptor_loss	0.9900
17:35101367:T:G	acceptor_loss	0.9900
17:35103239:AG:A	donor_gain	0.9900
17:35103448:ACTC:A	donor_loss	0.9900
17:35103450:TCA:T	donor_loss	0.9900

AlphaMissense

2087 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:35101302:A:G	W268R	0.996
17:35101302:A:T	W268R	0.996
17:35101280:C:G	R275P	0.991
17:35101300:C:A	W268C	0.991
17:35101300:C:G	W268C	0.991
17:35107373:T:A	K113I	0.991
17:35101289:G:T	P272H	0.989
17:35101357:G:C	N249K	0.989
17:35101357:G:T	N249K	0.989
17:35107370:G:A	T114I	0.989
17:35107117:A:C	C117W	0.988
17:35103504:T:A	D206V	0.986
17:35103291:A:G	L234P	0.985
17:35107119:A:G	C117R	0.985
17:35118561:C:T	G68D	0.985
17:35119163:A:G	L31P	0.985
17:35103498:A:T	V208D	0.984
17:35118594:A:G	L57P	0.984
17:35101289:G:C	P272R	0.983
17:35103505:C:G	D206H	0.983
17:35101213:T:A	K297N	0.982
17:35101213:T:G	K297N	0.982
17:35107372:T:A	K113N	0.979
17:35107372:T:G	K113N	0.979
17:35107400:T:A	E104V	0.979
17:35107443:C:G	D90H	0.978
17:35103502:A:G	S207P	0.977
17:35103504:T:G	D206A	0.977
17:35107391:C:T	G107E	0.977
17:35107068:A:C	Y134D	0.976

dbSNP variants (sampled 300 via entrez): RS1000144280 (17:35098390 A>C,G), RS1000155555 (17:35098017 G>A,T), RS1000451828 (17:35097144 G>A), RS1000477889 (17:35113347 C>A), RS1000642028 (17:35094087 G>T), RS1000776325 (17:35097384 C>T), RS1000856198 (17:35110609 G>A), RS1000923742 (17:35107248 C>A,T), RS1001185834 (17:35108942 T>C), RS1001207818 (17:35105912 A>G), RS1001264147 (17:35115178 C>A), RS1001328746 (17:35116479 A>T), RS1001371878 (17:35101923 G>A), RS1001375695 (17:35091994 T>C), RS1001440122 (17:35103328 C>A,G,T)

Disease associations

OMIM: gene MIM:602954 | disease phenotypes: MIM:614291, MIM:613659, MIM:120435, MIM:114500, MIM:604370, MIM:613095

GenCC curated gene-disease

Disease	Classification	Inheritance
breast-ovarian cancer, familial, susceptibility to, 4	Strong	Autosomal dominant
hereditary breast ovarian cancer syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
RAD51D-related cancer predisposition	Definitive	AD

Mondo (20): breast-ovarian cancer, familial, susceptibility to, 4 (MONDO:0013669), hereditary neoplastic syndrome (MONDO:0015356), gastric cancer (MONDO:0001056), ovarian carcinoma (MONDO:0005140), hereditary breast ovarian cancer syndrome (MONDO:0003582), breast cancer (MONDO:0007254), familial ovarian cancer (MONDO:0016248), Lynch syndrome 1 (MONDO:0007356), anaplastic/large cell medulloblastoma (MONDO:0016709), colorectal cancer (MONDO:0005575), ovarian neoplasm (MONDO:0021068), diffuse midline glioma, H3 K27-altered (MONDO:1060171), RAD51D-related cancer predisposition (MONDO:0700274), breast-ovarian cancer, familial, susceptibility to, 1 (MONDO:0011450), hereditary site-specific ovarian cancer syndrome (MONDO:0016249)

Orphanet (7): Hereditary breast and/or ovarian cancer syndrome (Orphanet:145), Inherited cancer-predisposing syndrome (Orphanet:140162), Lynch syndrome (Orphanet:144), Anaplastic/large cell medulloblastoma (Orphanet:251855), OBSOLETE: Familial ovarian cancer (Orphanet:213517), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667), Hereditary site-specific ovarian cancer syndrome (Orphanet:213524)

HPO phenotypes

7 total (7 of 7 shown, HPO-id order):

HPO	Term
HP:0002861	Melanoma
HP:0002894	Neoplasm of the pancreas
HP:0003002	Breast carcinoma
HP:0011027	Abnormal fallopian tube morphology
HP:0012125	Prostate cancer
HP:0030406	Primary peritoneal carcinoma
HP:0100615	Ovarian neoplasm

GWAS associations

0 associations (top):

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
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
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700
C537261	Lynch syndrome I (site-specific colonic cancer) (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items; also 1 predisposing.

Variant	Therapy	Indication	Effect	Level	CIViC
RAD51D Mutation	Olaparib	Castration-resistant Prostate Carcinoma	Sensitivity/Response	CIViC A	EID11214

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression	2
apocarotenal	increases expression	1
triphenyl phosphate	affects expression	1
chlorophyllin	decreases reaction, increases expression	1
cobaltous chloride	decreases expression	1
polyhexamethyleneguanidine	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
jinfukang	increases expression	1
Zoledronic Acid	increases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Atrazine	decreases expression	1
Benzo(a)pyrene	decreases reaction, increases expression	1
Ethyl Methanesulfonate	increases expression	1
Methyl Methanesulfonate	increases expression	1
Ozone	increases abundance, affects expression	1
Tetrachlorodibenzodioxin	affects expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases expression	1
beta Carotene	increases expression	1
Cadmium Chloride	decreases expression	1
Copper Sulfate	decreases expression	1
Acrylamide	decreases expression	1
Particulate Matter	decreases expression	1

Cellosaurus cell lines

7 cell lines: 5 cancer cell line, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B8NK	Abcam HCT 116 RAD51D KO	Cancer cell line	Male
CVCL_B9AY	Abcam MCF-7 RAD51D KO	Cancer cell line	Female
CVCL_B9QW	Abcam A-549 RAD51D KO	Cancer cell line	Male
CVCL_VR82	U2OS#18-RAD51D-4	Cancer cell line	Female
CVCL_VR83	U2OS#18-RAD51D-4/D+	Cancer cell line	Female
CVCL_XX03	HEK293-DR-GFP-RAD51D-16	Transformed cell line	Female
CVCL_XX08	HEK293-DR-GFP-RAD51D-16/D+	Transformed cell line	Female

Clinical trials (associated diseases)

348 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
NCT00365508	PHASE4	COMPLETED	Counseling and Nicotine Replacement Therapy in Helping Adult Smokers Quit Smoking
NCT00558155	PHASE4	COMPLETED	The Impact of Immunostimulating Nutrition on the Outcome of Surgery
NCT00576940	PHASE4	COMPLETED	Standard and Immunostimulating Enteral Nutrition in Surgical Patients
NCT00666978	PHASE4	COMPLETED	Health Education Counseling With or Without Bupropion in Helping African Americans Stop Smoking
NCT01038154	PHASE4	UNKNOWN	Study to Evaluate the Efficacy of Pravastatin on Survival and Recurrence of Advanced Gastroesophageal Cancer
NCT01234272	PHASE4	COMPLETED	Comparison of the Analgesic Effect Between Intrathecal Morphine and IV-fentanyl Patient Controlled Analgesia (ITM-IVPCA) and Epidural PCA (PCEA) in Patients Undergoing Gastrectomy -Randomized Allocation Study-
NCT01260194	PHASE4	TERMINATED	A Study of Herceptin (Trastuzumab) in Combination With Standard Chemotherapy in Patients With HER Positive Metastatic Gastric Cancer
NCT01271582	PHASE4	UNKNOWN	Investigation of Association Between UGT1A1 Polymorphisms and Irinotecan Toxicity in Korean Patients
NCT01401075	PHASE4	COMPLETED	RCT With Adjuvant Mistletoe Treatment in Gastric Cancer Patients
NCT01471756	PHASE4	COMPLETED	Improving Complete Endoscopic Mucosal Resection (EMR) of Colorectal Neoplasia
NCT01766765	PHASE4	UNKNOWN	Early Jejunostomy Nutrition Minimizes Time to Chemotherapy
NCT01910948	PHASE4	UNKNOWN	Perioperative Application of Omega-3 Polyunsaturated Fatty Acids in Gastric Cancer Patients
NCT01927328	PHASE4	UNKNOWN	Iron Replacement in Oesophagogastric Neoplasia
NCT01962272	PHASE4	COMPLETED	The Effect of Nutritional Counseling for Cancer Patients
NCT01962376	PHASE4	UNKNOWN	Preoperative Chemotherapy With Bevacizumab For Potentially Resectable Gastric Cancer With Liver Metastasis
NCT02047994	PHASE4	RECRUITING	Multicentric Randomized Study of H. Pylori Eradication and Pepsinogen Testing for Prevention of Gastric Cancer Mortality
NCT02235246	PHASE4	COMPLETED	The Effect of Perioperative Intravenous Magnesium on Pain After Endoscopic Submucosal Dissection for Gastric Neoplasm: Prospective Randomized Double-blind Placebo Controlled Study
NCT02366819	PHASE4	SUSPENDED	Genetic Analysis-Guided Irinotecan Hydrochloride Dosing of mFOLFIRINOX in Treating Patients With Locally Advanced Gastroesophageal or Stomach Cancer
NCT02401971	PHASE4	UNKNOWN	Irinotecan Plus Thalidomide in Second Line Advanced Gastric Cancer
NCT02458573	PHASE4	COMPLETED	Comparison of the Effects of Continuous Epidural Analgesia and Continuous Intravenous Analgesia on Postoperative Bowel Movement in Patients Undergoing Laparoscopic Gastrectomy
NCT02638584	PHASE4	COMPLETED	Effects of Ilaprazole on Ulcer Healing Rate and Prevention of Gastrointestinal Bleeding in the Patients Undergone ESD.
NCT02776527	PHASE4	UNKNOWN	A Clinical Trial of Maintenance Treatment of Apatinib in Advanced Gastric Cancer Patients Have Completed Postoprative Adjuvant Chemotherapy
NCT03384511	PHASE4	COMPLETED	The Use of 18F-ALF-NOTA-PRGD2 PET/CT Scan to Predict the Efficacy and Adverse Events of Apatinib in Malignancies.
NCT03550482	PHASE4	COMPLETED	Oncoxin® and Quality of Life in Cancer Patients
NCT03609892	PHASE4	COMPLETED	Helicobacter Rescue Therapy With Berberine Plus Amoxicillin Quadruple Therapy Versus Tetracycline Plus Furazolidone Quadruple Therapy
NCT03642093	PHASE4	UNKNOWN	HOPE - A Study to Evaluate the Effect of a Prehabilitation Program on GI Cancer Patients Planning to Undergo Surgery
NCT03733639	PHASE4	UNKNOWN	Tisseel® as a Reinforcement of Esophagojejunal Anastomoses
NCT04168346	PHASE4	NOT_YET_RECRUITING	Preoperative Intravenous Iron Therapy in Patients With Gastric Cancer
NCT04209933	PHASE4	COMPLETED	Helicobacter Pylori Eradication With Different Bismuth Quadruple Therapies
NCT04591028	PHASE4	WITHDRAWN	A Study to Evaluate Indocyanine Green Lymphangiography to Improve Lymphadenectomy in Gastric Cancer Patients
NCT04607057	PHASE4	UNKNOWN	Supplemental Parenteral Nutrition During Postgastrectomy in Nutritionally at Risk Patient
NCT04660123	PHASE4	COMPLETED	A Real World Study of Bismuth Colloidal Pectin Granules Quadruple Therapy for H. Pylori Eradication
NCT04678492	PHASE4	COMPLETED	Helicobacter Rescue Therapy With High-dose Esomeprazole and Amoxicillin Dual Therapy Versus Bismuth-containing Quadruple Therapy
NCT04697186	PHASE4	COMPLETED	Helicobacter Pylori Eradication With Berberine Plus Amoxicillin Triple Therapy Versus Bismuth-containing Quadruple Therapy
NCT05029453	PHASE4	UNKNOWN	Apatinib Combined With Chemotherapy Versus Chemotherapy in Second-line Gastric Cancer Receiving Prior Anti-PD-1 Therapy
NCT05183126	PHASE4	RECRUITING	Pharmacokinetic Study of Skeletal Muscle Area-based Paclitaxel Infusion in Patients With Cancer
NCT05354856	PHASE4	TERMINATED	The Effect of Chemoradiotherapy on Gastric Perfusion in Patients With Gastric Cancer.
NCT05410535	PHASE4	COMPLETED	To Evaluate Efficacy of Ursodeoxycholic Acid (UDCA) for the Prevention of Gallstone Formation After Gasterectomy
NCT05498766	PHASE4	NOT_YET_RECRUITING	Effect and Safety of Huaier Granule Versus SOX Regimen in Gastric Cancer Patients