Fanconi anemia complementation group O

Summary

Fanconi anemia complementation group O (MONDO:0013248) is a disease caused by RAD51C (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: RAD51C (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 1,695

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Fanconi anemia complementation group O
Mondo ID	MONDO:0013248
OMIM	613390
DOID	DOID:0111096
UMLS	C3150653
MedGen	462003
GARD	0015656
Is cancer (heuristic)	no

Also known as: FANCO · Fanconi anaemia caused by mutation in RAD51C · Fanconi anaemia caused by mutation in Rad51C · Fanconi anaemia complementation group type O · Fanconi anemia caused by mutation in RAD51C · Fanconi anemia caused by mutation in Rad51C · Fanconi anemia complementation group type O · Fanconi anemia, complementation group O · Fanconi Anemia, complementation group type O · RAD51C Fanconi anaemia · Rad51C Fanconi anaemia · RAD51C Fanconi anemia · Rad51C Fanconi anemia

Data availability: 1,695 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › congenital anemia › Fanconi anemia › Fanconi anemia complementation group O

Related subtypes (21): Fanconi anemia complementation group C, Fanconi anemia complementation group D2, Fanconi anemia complementation group A, Fanconi anemia complementation group B, Fanconi anemia complementation group E, Fanconi anemia complementation group F, Fanconi anemia complementation group D1, Fanconi anemia complementation group I, Fanconi anemia complementation group J, Fanconi anemia complementation group N, Fanconi anemia complementation group P, Fanconi anemia complementation group G, Fanconi anemia complementation group L, Fanconi anemia complementation group Q, Fanconi anemia complementation group T, Fanconi anemia complementation group V, Fanconi anemia complementation group R, Fanconi anemia complementation group U, Fanconi anemia, complementation group W, Fanconi anemia, complementation group S, fanconi anemia, complementation group 10

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

182 uncertain significance, 148 conflicting classifications of pathogenicity, 111 likely benign, 72 benign/likely benign, 54 pathogenic, 26 pathogenic/likely pathogenic, 6 likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1072935	NM_058216.3(RAD51C):c.612del (p.Leu205fs)	LOC129390903	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1098903	NM_058216.3(RAD51C):c.656T>A (p.Leu219Ter)	LOC129390903	Pathogenic	criteria provided, multiple submitters, no conflicts
1098905	NM_058216.3(RAD51C):c.704dup (p.Val236fs)	LOC129390903	Pathogenic	criteria provided, multiple submitters, no conflicts
1098906	NM_058216.3(RAD51C):c.705+1G>T	LOC129390903	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1401730	NM_058216.3(RAD51C):c.688del (p.Leu230fs)	LOC129390903	Pathogenic	criteria provided, single submitter
142919	NM_058216.3(RAD51C):c.701C>G (p.Ser234Ter)	LOC129390903	Pathogenic	criteria provided, multiple submitters, no conflicts
1439892	NM_058216.3(RAD51C):c.692del (p.Leu230_Ser231insTer)	LOC129390903	Pathogenic	criteria provided, single submitter
1751885	NM_058216.3(RAD51C):c.615_616del (p.His207fs)	LOC129390903	Pathogenic	criteria provided, multiple submitters, no conflicts
185074	NM_058216.3(RAD51C):c.630T>G (p.Tyr210Ter)	LOC129390903	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
186604	NM_058216.3(RAD51C):c.653_654del (p.Glu218fs)	LOC129390903	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2021697	NM_058216.3(RAD51C):c.615_618del (p.Ser206fs)	LOC129390903	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
219702	NM_058216.1(RAD51C):c.(?_-1)_837+?del	LOC129390903	Pathogenic	criteria provided, single submitter
1069820	NM_058216.3(RAD51C):c.472dup (p.Ile158fs)	RAD51C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069913	NM_058216.3(RAD51C):c.961C>T (p.Gln321Ter)	RAD51C	Pathogenic	criteria provided, multiple submitters, no conflicts
1071025	NC_000017.10:g.(?56798097)(56801482_?)del	RAD51C	Pathogenic	criteria provided, single submitter
1072950	NM_058216.3(RAD51C):c.401T>G (p.Leu134Ter)	RAD51C	Pathogenic	criteria provided, multiple submitters, no conflicts
1073709	NM_058216.3(RAD51C):c.795del (p.Ala266fs)	RAD51C	Pathogenic	criteria provided, multiple submitters, no conflicts
1074936	NC_000017.10:g.(?56780551)(56787357_?)del	RAD51C	Pathogenic	criteria provided, single submitter
1075016	NM_058216.3(RAD51C):c.905-1G>A	RAD51C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076896	NC_000017.10:g.(?56769920)(56811662_?)del	RAD51C	Pathogenic	criteria provided, single submitter
1098899	NM_058216.3(RAD51C):c.572-1G>T	RAD51C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1098907	NM_058216.3(RAD51C):c.706-1G>A	RAD51C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1171281	NM_058216.3(RAD51C):c.917del (p.Gly306fs)	RAD51C	Pathogenic	criteria provided, multiple submitters, no conflicts
1209850	NM_058216.3(RAD51C):c.907G>T (p.Glu303Ter)	RAD51C	Pathogenic	criteria provided, single submitter
128201	NM_058216.3(RAD51C):c.1026+5_1026+7del	RAD51C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
128209	NM_058216.3(RAD51C):c.706-2A>G	RAD51C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
136163	NM_058216.3(RAD51C):c.97_98del (p.Gln33fs)	RAD51C	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1364557	NM_058216.3(RAD51C):c.915G>A (p.Trp305Ter)	RAD51C	Pathogenic	criteria provided, multiple submitters, no conflicts
1365075	NM_058216.3(RAD51C):c.496del (p.Val166fs)	RAD51C	Pathogenic	criteria provided, single submitter
1391838	NM_058216.3(RAD51C):c.981C>A (p.Tyr327Ter)	RAD51C	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RAD51C	Strong	Autosomal recessive	Fanconi anemia complementation group O	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RAD51C	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
RAD51C	Orphanet:84	Fanconi anemia
SEPTIN4	Orphanet:171709	Male infertility due to globozoospermia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RAD51C	HGNC:9820	ENSG00000108384	O43502	DNA repair protein RAD51 homolog 3	gencc,clinvar
SEPTIN4	HGNC:9165	ENSG00000108387	O43236	Septin-4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RAD51C	DNA repair protein RAD51 homolog 3	Essential for the homologous recombination (HR) pathway of DNA repair.
SEPTIN4	Septin-4	Filament-forming cytoskeletal GTPase.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RAD51C	Other/Unknown	no		Rad51_C, DNA_recomb/repair_RecA-like, RecA_ATP-bd
SEPTIN4	Other/Unknown	no		Septin, P-loop_NTPase, G_SEPTIN_dom

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
right testis	1
C1 segment of cervical spinal cord	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RAD51C	281	ubiquitous	marker	primordial germ cell in gonad, right testis, male germ line stem cell (sensu Vertebrata) in testis
SEPTIN4	225	broad	marker	C1 segment of cervical spinal cord, right hemisphere of cerebellum, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RAD51C	3,396
SEPTIN4	1,283

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RAD51C	O43502	17
SEPTIN4	O43236	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Release of apoptotic factors from the mitochondria	1	815.7×	0.008	SEPTIN4
SMAC, XIAP-regulated apoptotic response	1	815.7×	0.008	SEPTIN4
Impaired BRCA2 binding to PALB2	1	228.4×	0.009	RAD51C
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	1	211.5×	0.009	RAD51C
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	1	211.5×	0.009	RAD51C
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	1	211.5×	0.009	RAD51C
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	196.9×	0.009	RAD51C
Homologous DNA Pairing and Strand Exchange	1	190.3×	0.009	RAD51C
Resolution of D-loop Structures through Holliday Junction Intermediates	1	150.3×	0.010	RAD51C
Presynaptic phase of homologous DNA pairing and strand exchange	1	135.9×	0.010	RAD51C
HDR through Homologous Recombination (HRR)	1	95.2×	0.012	RAD51C
Meiotic recombination	1	64.9×	0.017	RAD51C
Factors involved in megakaryocyte development and platelet production	1	33.2×	0.030	RAD51C

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
meiotic DNA recombinase assembly	1	8426.0×	0.001	RAD51C
female meiosis sister chromatid cohesion	1	8426.0×	0.001	RAD51C
spermatid differentiation	1	842.6×	0.007	SEPTIN4
telomere maintenance via recombination	1	766.0×	0.007	RAD51C
cytoskeleton-dependent cytokinesis	1	401.2×	0.007	SEPTIN4
sister chromatid cohesion	1	383.0×	0.007	RAD51C
regulation of exocytosis	1	351.1×	0.007	SEPTIN4
positive regulation of G2/M transition of mitotic cell cycle	1	300.9×	0.007	RAD51C
male meiosis I	1	290.6×	0.007	RAD51C
reciprocal meiotic recombination	1	280.9×	0.007	RAD51C
hematopoietic stem cell homeostasis	1	280.9×	0.007	SEPTIN4
positive regulation of intrinsic apoptotic signaling pathway	1	240.7×	0.008	SEPTIN4
DNA recombination	1	168.5×	0.010	RAD51C
positive regulation of protein ubiquitination	1	106.7×	0.015	SEPTIN4
double-strand break repair via homologous recombination	1	78.0×	0.020	RAD51C
neuron migration	1	66.9×	0.021	SEPTIN4
flagellated sperm motility	1	58.5×	0.023	SEPTIN4
intracellular protein localization	1	52.3×	0.024	SEPTIN4
regulation of apoptotic process	1	41.7×	0.029	SEPTIN4
DNA repair	1	31.9×	0.036	RAD51C
positive regulation of apoptotic process	1	28.4×	0.038	SEPTIN4
spermatogenesis	1	17.6×	0.059	RAD51C
apoptotic process	1	14.3×	0.068	SEPTIN4

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RAD51C	0	0
SEPTIN4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	RAD51C, SEPTIN4

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
RAD51C	0	—
SEPTIN4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.