Fanconi anemia complementation group I

Summary

Fanconi anemia complementation group I (MONDO:0012186) is a disease caused by FANCI (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: FANCI (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 640

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Fanconi anemia complementation group I
Mondo ID	MONDO:0012186
MeSH	C563802
OMIM	609053
DOID	DOID:0111091
NCIT	C129026
UMLS	C1836861
MedGen	323016
GARD	0015448
Is cancer (heuristic)	no

Also known as: FANCI · Fanconi anaemia complementation group type I · Fanconi anemia complementation group I · Fanconi anemia complementation group type I · Fanconi anemia, complementation group I · Fanconi Anemia, complementation group type 1

Data availability: 640 ClinVar variants · 4 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 I

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 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

600 retrieved; paginated sample, class counts are floors:

330 uncertain significance, 90 likely pathogenic, 52 conflicting classifications of pathogenicity, 45 pathogenic/likely pathogenic, 30 likely benign, 26 benign/likely benign, 19 benign, 7 pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1031096	NM_001113378.2(FANCI):c.2737C>T (p.Gln913Ter)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070880	NM_001113378.2(FANCI):c.3622dup (p.Leu1208fs)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073102	NM_001113378.2(FANCI):c.2695_2698del (p.Glu899fs)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1224538	NM_001113378.2(FANCI):c.295del (p.His99fs)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1224539	NM_001113378.2(FANCI):c.3907G>T (p.Glu1303Ter)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324384	NM_001113378.2(FANCI):c.3676dup (p.Thr1226fs)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1378855	NM_001113378.2(FANCI):c.2858dup (p.Arg954fs)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1397747	NM_001113378.2(FANCI):c.511C>T (p.Gln171Ter)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1404698	NM_001113378.2(FANCI):c.834del (p.Ile279fs)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1420083	NM_001113378.2(FANCI):c.886G>T (p.Gly296Ter)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1425245	NM_001113378.2(FANCI):c.2345_2346del (p.Leu781_Ser782insTer)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1438031	NM_001113378.2(FANCI):c.3118_3119del (p.Lys1040fs)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1441734	NM_001113378.2(FANCI):c.998C>A (p.Ser333Ter)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451296	NM_001113378.2(FANCI):c.3623dup (p.Cys1209fs)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1702568	NM_001113378.2(FANCI):c.3801_3804del (p.Ser1268fs)	FANCI	Pathogenic	criteria provided, multiple submitters, no conflicts
2064506	NM_001113378.2(FANCI):c.3184C>T (p.Gln1062Ter)	FANCI	Pathogenic	criteria provided, multiple submitters, no conflicts
2073790	NM_001113378.2(FANCI):c.349A>T (p.Arg117Ter)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208639	NM_001113378.2(FANCI):c.2422A>T (p.Lys808Ter)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2169244	NM_001113378.2(FANCI):c.2467C>T (p.Gln823Ter)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2191991	NM_001113378.2(FANCI):c.2635C>T (p.Arg879Ter)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
219634	NM_001113378.2(FANCI):c.3626_3627del (p.Cys1209fs)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225355	NM_001113378.2(FANCI):c.158-2A>G	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2675598	NM_001113378.2(FANCI):c.446del	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2675600	NM_001113378.2(FANCI):c.490del (p.Leu164fs)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2675611	NM_001113378.2(FANCI):c.3147del (p.Leu1049fs)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2675616	NM_001113378.2(FANCI):c.1897C>T (p.Gln633Ter)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2675617	NM_001113378.2(FANCI):c.2831_2834del (p.Arg944fs)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2675623	NM_001113378.2(FANCI):c.238dup (p.Asp80fs)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2675631	NM_001113378.2(FANCI):c.2680G>T (p.Glu894Ter)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2675632	NM_001113378.2(FANCI):c.2097C>G (p.Tyr699Ter)	FANCI	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 9 · 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
FANCI	Definitive	Autosomal recessive	Fanconi anemia complementation group I	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FANCI	Orphanet:84	Fanconi anemia
POLG	Orphanet:254881	Spinocerebellar ataxia with epilepsy
POLG	Orphanet:254886	Autosomal recessive progressive external ophthalmoplegia
POLG	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
POLG	Orphanet:298	Mitochondrial neurogastrointestinal encephalomyopathy
POLG	Orphanet:402082	Progressive myoclonic epilepsy type 5
POLG	Orphanet:70595	Sensory ataxic neuropathy-dysarthria-ophthalmoparesis syndrome
POLG	Orphanet:726	Alpers-Huttenlocher syndrome
POLG	Orphanet:94125	Recessive mitochondrial ataxia syndrome

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
FANCI	HGNC:25568	ENSG00000140525	Q9NVI1	Fanconi anemia group I protein	gencc,clinvar
POLG	HGNC:9179	ENSG00000140521	P54098	DNA polymerase subunit gamma-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FANCI	Fanconi anemia group I protein	Plays an essential role in the repair of DNA double-strand breaks by homologous recombination and in the repair of interstrand DNA cross-links (ICLs) by promoting FANCD2 monoubiquitination by FANCL and participating in recruitment to DNA r…
POLG	DNA polymerase subunit gamma-1	Catalytic subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA).

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)
FANCI	Other/Unknown	no		FANCI, FANCI_S1-cap, FANCI_S1
POLG	Other/Unknown	no		DNA-dir_DNA_pol_A_palm_dom, DNA-dir_DNA_pol_A_mt, RNaseH-like_sf

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
secondary oocyte	1
ventricular zone	1
granulocyte	1
small intestine Peyer’s patch	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FANCI	221	ubiquitous	marker	ventricular zone, secondary oocyte, male germ line stem cell (sensu Vertebrata) in testis
POLG	295	ubiquitous	marker	granulocyte, small intestine Peyer’s patch, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLG	3,400
FANCI	2,312

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLG	P54098	36
FANCI	Q9NVI1	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Strand-asynchronous mitochondrial DNA replication	1	571.0×	0.005	POLG
Fanconi Anemia Pathway	1	139.3×	0.011	FANCI
TP53 Regulates Transcription of DNA Repair Genes	1	90.6×	0.011	FANCI

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
DNA replication proofreading	1	2808.7×	0.003	POLG
mitochondrial DNA replication	1	766.0×	0.004	POLG
base-excision repair, gap-filling	1	561.7×	0.004	POLG
DNA metabolic process	1	526.6×	0.004	POLG
DNA-templated DNA replication	1	280.9×	0.005	POLG
base-excision repair	1	234.1×	0.005	POLG
interstrand cross-link repair	1	216.1×	0.005	FANCI
positive regulation of protein ubiquitination	1	106.7×	0.009	FANCI

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
POLG	ADEFOVIR DIPIVOXIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
POLG	1	4
FANCI	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ADEFOVIR DIPIVOXIL	4	POLG

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
POLG	33	Binding:30, ADMET:2, Functional:1
FANCI	1	Binding:1

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

1 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.

Compound	Max phase	Cohort target (bioactivity)
ADEFOVIR DIPIVOXIL	4	POLG

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	POLG
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	1	FANCI

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FANCI	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.