Fanconi anemia complementation group D2

Summary

Fanconi anemia complementation group D2 (MONDO:0009214) is a disease caused by FANCD2 (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: FANCD2 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 599

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Fanconi anemia complementation group D2
Mondo ID	MONDO:0009214
OMIM	227646
DOID	DOID:0111083
NCIT	C125706
UMLS	C3160738
MedGen	463627
GARD	0015169
Is cancer (heuristic)	no

Also known as: FA4 · FAD2 · FANCD2 · Fanconi anemia complementation group D2 · Fanconi anemia, complementation group D2

Data availability: 599 ClinVar variants · 5 GenCC gene-disease records · 4 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › congenital anemia › Fanconi anemia › Fanconi anemia complementation group D2

Related subtypes (21): Fanconi anemia complementation group C, 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 O, 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

599 retrieved; paginated sample, class counts are floors:

269 uncertain significance, 83 likely pathogenic, 74 conflicting classifications of pathogenicity, 46 pathogenic/likely pathogenic, 33 likely benign, 33 pathogenic, 31 benign, 30 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
434539	NM_032043.3(BRIP1):c.1741C>T (p.Arg581Ter)	BRIP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1070165	NM_001018115.3(FANCD2):c.3799del (p.Tyr1267fs)	FANCD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071033	NM_001018115.3(FANCD2):c.3888+2T>G	FANCD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073865	NM_001018115.3(FANCD2):c.3922C>T (p.Gln1308Ter)	FANCD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075925	NM_001018115.3(FANCD2):c.2845G>T (p.Glu949Ter)	FANCD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076243	NM_001018115.3(FANCD2):c.1883_1884dup (p.Ala629fs)	FANCD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12038	NM_001018115.3(FANCD2):c.3707G>A (p.Arg1236His)	FANCD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12040	NM_001018115.3(FANCD2):c.904C>T (p.Arg302Trp)	FANCD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12041	NM_001018115.3(FANCD2):c.958C>T (p.Gln320Ter)	FANCD2	Pathogenic	criteria provided, multiple submitters, no conflicts
12042	NM_001018115.1:c.1414_1545del	FANCD2	Pathogenic	no assertion criteria provided
1298904	NM_001018115.3(FANCD2):c.3481C>T (p.Gln1161Ter)	FANCD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322877	NM_001018115.3(FANCD2):c.230del (p.Lys77fs)	FANCD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322878	NM_001018115.3(FANCD2):c.2160del (p.Gly721fs)	FANCD2	Pathogenic	criteria provided, single submitter
1322879	NM_001018115.3(FANCD2):c.99_102del (p.Lys33fs)	FANCD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322880	NM_001018115.3(FANCD2):c.3299_3300del (p.Gln1100fs)	FANCD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1322882	NM_001018115.3(FANCD2):c.2977-2A>G	FANCD2	Pathogenic	criteria provided, single submitter
1322883	NM_001018115.3(FANCD2):c.3500G>A (p.Trp1167Ter)	FANCD2	Pathogenic	criteria provided, multiple submitters, no conflicts
1322885	NM_001018115.3(FANCD2):c.2380C>T (p.Arg794Ter)	FANCD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324377	NM_001018115.3(FANCD2):c.505G>T (p.Glu169Ter)	FANCD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324378	NM_001018115.3(FANCD2):c.92del (p.Lys31fs)	FANCD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324381	NM_001018115.3(FANCD2):c.3817C>T (p.Arg1273Ter)	FANCD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1449465	NM_001018115.3(FANCD2):c.1866_1867delinsAT (p.Gln623Ter)	FANCD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685810	NM_001018115.3(FANCD2):c.1279-1G>A	FANCD2	Pathogenic	criteria provided, single submitter
1690778	NM_001018115.3(FANCD2):c.1068T>A (p.Tyr356Ter)	FANCD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2077162	NM_001018115.3(FANCD2):c.2757dup (p.Asn920Ter)	FANCD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2079849	NM_001018115.3(FANCD2):c.3289C>T (p.Arg1097Ter)	FANCD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
241735	NM_001018115.3(FANCD2):c.2444G>A (p.Arg815Gln)	FANCD2	Pathogenic	criteria provided, multiple submitters, no conflicts
2675482	NM_001018115.3(FANCD2):c.2776C>T (p.Arg926Ter)	FANCD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2675489	NM_033084.6(FANCD2):c.2609_2613del	FANCD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2675490	NM_001018115.3(FANCD2):c.4090del (p.Leu1364fs)	FANCD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 7 · 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
FANCD2	Definitive	Autosomal recessive	Fanconi anemia complementation group D2	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FANCD2	Orphanet:84	Fanconi anemia
BRIP1	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
BRIP1	Orphanet:84	Fanconi anemia
PEX5	Orphanet:44	Neonatal adrenoleukodystrophy
PEX5	Orphanet:468717	Rhizomelic chondrodysplasia punctata type 5
PEX5	Orphanet:772	Infantile Refsum disease
PEX5	Orphanet:912	Zellweger syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FANCD2	HGNC:3585	ENSG00000144554	Q9BXW9	Fanconi anemia group D2 protein	gencc,clinvar
BRIP1	HGNC:20473	ENSG00000136492	Q9BX63	Fanconi anemia group J protein	clinvar
FANCD2OS	HGNC:28623	ENSG00000163705	Q96PS1	FANCD2 opposite strand protein	clinvar
PEX5	HGNC:9719	ENSG00000139197	P50542	Peroxisomal targeting signal 1 receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FANCD2	Fanconi anemia group D2 protein	Required for maintenance of chromosomal stability.
BRIP1	Fanconi anemia group J protein	DNA-dependent ATPase and 5’-3’ DNA helicase required for the maintenance of chromosomal stability.
FANCD2OS	FANCD2 opposite strand protein	Reduces testosterone levels by inhibiting steroidogenic enzymes and by promoting apoptosis in Leydig cells.
PEX5	Peroxisomal targeting signal 1 receptor	Receptor that mediates peroxisomal import of proteins containing a C-terminal PTS1-type tripeptide peroxisomal targeting signal (SKL-type).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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
Enzyme (other)	1	3.0×	0.404
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FANCD2	Other/Unknown	no		FANCD2
BRIP1	Enzyme (other)	yes	3.6.4.12	Helicase-like_DEXD_c2, ATP-dep_Helicase_C, RAD3-like_helicase_DEAD
FANCD2OS	Other/Unknown	no		FANCD2OS
PEX5	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, PEX5/PEX5L

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	2
ventricular zone	2
left testis	2
right testis	2
secondary oocyte	1
primordial germ cell in gonad	1
testis	1
gastrocnemius	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FANCD2	200	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, ventricular zone, secondary oocyte
BRIP1	181	ubiquitous	marker	ventricular zone, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
FANCD2OS	120	tissue_specific	marker	left testis, right testis, testis
PEX5	142	ubiquitous	marker	gastrocnemius, left testis, right testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FANCD2	3,820
BRIP1	2,272
PEX5	1,741
FANCD2OS	349

Intra-cohort edges

A	B	Sources
BRIP1	FANCD2	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FANCD2	Q9BXW9	13
PEX5	P50542	11
BRIP1	Q9BX63	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FANCD2OS	Q96PS1	61.31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Pexophagy	1	317.2×	0.017	PEX5
Cytosolic iron-sulfur cluster assembly	1	253.8×	0.017	BRIP1
Impaired BRCA2 binding to PALB2	1	152.3×	0.017	BRIP1
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	1	141.0×	0.017	BRIP1
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	1	141.0×	0.017	BRIP1
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	1	141.0×	0.017	BRIP1
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	131.3×	0.017	BRIP1
Homologous DNA Pairing and Strand Exchange	1	126.9×	0.017	BRIP1
Impaired BRCA2 binding to RAD51	1	102.9×	0.017	BRIP1
Resolution of D-loop Structures through Holliday Junction Intermediates	1	100.2×	0.017	BRIP1
HDR through Single Strand Annealing (SSA)	1	97.6×	0.017	BRIP1
Fanconi Anemia Pathway	1	92.8×	0.017	FANCD2
Presynaptic phase of homologous DNA pairing and strand exchange	1	90.6×	0.017	BRIP1
E3 ubiquitin ligases ubiquitinate target proteins	1	64.5×	0.020	PEX5
HDR through Homologous Recombination (HRR)	1	63.4×	0.020	BRIP1
TP53 Regulates Transcription of DNA Repair Genes	1	60.4×	0.020	FANCD2
Peroxisomal protein import	1	57.7×	0.020	PEX5
G2/M DNA damage checkpoint	1	40.1×	0.026	BRIP1
Regulation of TP53 Activity through Phosphorylation	1	39.2×	0.026	BRIP1
Processing of DNA double-strand break ends	1	38.1×	0.026	BRIP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
double-strand break repair involved in meiotic recombination	2	648.1×	2e-04	FANCD2, BRIP1
meiotic DNA double-strand break processing involved in reciprocal meiotic recombination	1	1404.3×	0.007	BRIP1
protein import into peroxisome matrix, docking	1	1053.2×	0.007	PEX5
protein import into peroxisome matrix, translocation	1	1053.2×	0.007	PEX5
negative regulation of testosterone biosynthetic process	1	1053.2×	0.007	FANCD2OS
regulation of CD40 signaling pathway	1	1053.2×	0.007	FANCD2
spermatogonial cell division	1	842.6×	0.007	BRIP1
protein import into peroxisome matrix, substrate release	1	842.6×	0.007	PEX5
protein import into peroxisome membrane	1	702.2×	0.007	PEX5
mitochondrial membrane organization	1	601.9×	0.007	PEX5
protein import into peroxisome matrix, receptor recycling	1	601.9×	0.007	PEX5
regulation of regulatory T cell differentiation	1	468.1×	0.007	FANCD2
chiasma assembly	1	468.1×	0.007	BRIP1
protein targeting to peroxisome	1	421.3×	0.007	PEX5
protein-DNA covalent cross-linking repair	1	421.3×	0.007	BRIP1
cerebral cortex cell migration	1	383.0×	0.007	PEX5
protein import into peroxisome matrix	1	351.1×	0.007	PEX5
homologous recombination	1	351.1×	0.007	BRIP1
cerebral cortex neuron differentiation	1	300.9×	0.008	PEX5
pexophagy	1	263.3×	0.009	PEX5
mitotic intra-S DNA damage checkpoint signaling	1	234.1×	0.009	FANCD2
gamete generation	1	221.7×	0.009	FANCD2
cell development	1	221.7×	0.009	PEX5
very long-chain fatty acid metabolic process	1	191.5×	0.010	PEX5
seminiferous tubule development	1	191.5×	0.010	BRIP1
brain morphogenesis	1	183.2×	0.010	FANCD2
neuronal stem cell population maintenance	1	168.5×	0.010	FANCD2
protein tetramerization	1	156.0×	0.011	PEX5
homologous chromosome pairing at meiosis	1	150.5×	0.011	FANCD2
response to gamma radiation	1	145.3×	0.011	FANCD2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FANCD2	0	0
BRIP1	0	0
FANCD2OS	0	0
PEX5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
FANCD2	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BRIP1	3.6.4.12	DNA helicase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	1	BRIP1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	FANCD2, FANCD2OS, PEX5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FANCD2	2	—
BRIP1	0	—
FANCD2OS	0	—
PEX5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.