Karyomegalic interstitial nephritis

Summary

Karyomegalic interstitial nephritis (MONDO:0013898) is a disease caused by FAN1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: FAN1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 211

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		12	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	karyomegalic interstitial nephritis
Mondo ID	MONDO:0013898
OMIM	614817
Orphanet	401996
DOID	DOID:0060911
NCIT	C173626
UMLS	C3553774
MedGen	766688
GARD	0011003
Is cancer (heuristic)	no

Also known as: FAN1 interstitial nephritis · interstitial nephritis caused by mutation in FAN1 · interstitial nephritis, karyomegalic · karyomegalic interstitial nephritis · KIN · kin · KMIN · systemic karyomegaly

Data availability: 211 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › urinary system disorder › kidney disorder › nephritis › interstitial nephritis › karyomegalic interstitial nephritis

Related subtypes (1): Balkan nephropathy

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

211 retrieved; paginated sample, class counts are floors:

133 uncertain significance, 28 likely pathogenic, 15 pathogenic, 15 conflicting classifications of pathogenicity, 7 likely benign, 7 pathogenic/likely pathogenic, 3 benign/likely benign, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1179198	NM_014967.5(FAN1):c.1702C>T (p.Gln568Ter)	FAN1	Pathogenic	criteria provided, single submitter
1344663	NM_014967.5(FAN1):c.2590C>T (p.Gln864Ter)	FAN1	Pathogenic	criteria provided, single submitter
1926546	NM_014967.5(FAN1):c.2260C>T (p.Arg754Ter)	FAN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2137641	NM_014967.5(FAN1):c.2128C>T (p.Arg710Ter)	FAN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2637123	NM_014967.5(FAN1):c.141C>A (p.Cys47Ter)	FAN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3248651	NM_014967.5(FAN1):c.1369C>T (p.Gln457Ter)	FAN1	Pathogenic	criteria provided, multiple submitters, no conflicts
3376569	NM_014967.5(FAN1):c.322_323del (p.Asn108fs)	FAN1	Pathogenic	criteria provided, single submitter
3577021	NM_014967.5(FAN1):c.1943+1G>A	FAN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
37094	NM_014967.5(FAN1):c.2120G>A (p.Trp707Ter)	FAN1	Pathogenic	criteria provided, multiple submitters, no conflicts
37095	NM_014967.5(FAN1):c.1234+2T>A	FAN1	Pathogenic	no assertion criteria provided
37096	NM_014967.5(FAN1):c.2036_2037del (p.Arg679fs)	FAN1	Pathogenic	no assertion criteria provided
37097	NM_014967.5(FAN1):c.2245C>T (p.Arg749Ter)	FAN1	Pathogenic	criteria provided, multiple submitters, no conflicts
37099	NM_014967.5(FAN1):c.1375+1G>A	FAN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
37101	NM_014967.5(FAN1):c.2809G>C (p.Gly937Arg)	FAN1	Pathogenic	no assertion criteria provided
3775318	NM_014967.5(FAN1):c.1987_1996del (p.Gly663fs)	FAN1	Pathogenic	criteria provided, single submitter
421580	NM_014967.5(FAN1):c.922_923del (p.Val308fs)	FAN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4277813	NM_014967.5(FAN1):c.1480C>T (p.Gln494Ter)	FAN1	Pathogenic	criteria provided, single submitter
437428	NM_014967.5(FAN1):c.1102C>T (p.Gln368Ter)	FAN1	Pathogenic	criteria provided, single submitter
437429	NM_014967.5(FAN1):c.2616del (p.Asp873fs)	FAN1	Pathogenic	criteria provided, multiple submitters, no conflicts
817020	NM_014967.5(FAN1):c.1899del (p.Cys633fs)	FAN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
973638	NM_014967.5(FAN1):c.256_257del (p.Met86fs)	FAN1	Pathogenic	no assertion criteria provided
37100	NM_014967.5(FAN1):c.2774_2775del (p.Leu925fs)	MTMR10	Pathogenic	criteria provided, single submitter
1179186	NM_014967.5(FAN1):c.332del (p.Pro111fs)	FAN1	Likely pathogenic	criteria provided, single submitter
3576948	NM_014967.5(FAN1):c.28A>T (p.Lys10Ter)	FAN1	Likely pathogenic	criteria provided, single submitter
3576949	NM_014967.5(FAN1):c.31_34del (p.Lys11fs)	FAN1	Likely pathogenic	criteria provided, single submitter
3576950	NM_014967.5(FAN1):c.32_35del (p.Lys11fs)	FAN1	Likely pathogenic	criteria provided, single submitter
3576962	NM_014967.5(FAN1):c.346dup (p.Ser116fs)	FAN1	Likely pathogenic	criteria provided, single submitter
3576977	NM_014967.5(FAN1):c.652del (p.Cys218fs)	FAN1	Likely pathogenic	criteria provided, single submitter
3576982	NM_014967.5(FAN1):c.791dup (p.Leu264fs)	FAN1	Likely pathogenic	criteria provided, single submitter
3576985	NM_014967.5(FAN1):c.871G>T (p.Glu291Ter)	FAN1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
FAN1	Definitive	Autosomal recessive	karyomegalic interstitial nephritis	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FAN1	Orphanet:401996	Karyomegalic interstitial nephritis

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
FAN1	HGNC:29170	ENSG00000198690	Q9Y2M0	Fanconi-associated nuclease 1	gencc,clinvar
MTMR10	HGNC:25999	ENSG00000166912	Q9NXD2	Myotubularin-related protein 10	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FAN1	Fanconi-associated nuclease 1	Nuclease required for the repair of DNA interstrand cross-links (ICL) recruited at sites of DNA damage by monoubiquitinated FANCD2.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Phosphatase	1	42.0×	0.047
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FAN1	Other/Unknown	no		Rad18_UBZ4, tRNA_endonuc-like_dom_sf, VRR_NUC
MTMR10	Phosphatase	yes		Myotubularin-like_Pase_dom, PH-like_dom_sf, MTMR12-like_C

Expression context

Cohort genes with no expression data: 0.

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
gastrocnemius	1
pancreatic ductal cell	1
right hemisphere of cerebellum	1
corpus callosum	1
inferior vagus X ganglion	1
spinal cord	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FAN1	214	ubiquitous	yes	pancreatic ductal cell, right hemisphere of cerebellum, gastrocnemius
MTMR10	256	ubiquitous	yes	corpus callosum, inferior vagus X ganglion, spinal cord

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MTMR10	784
FAN1	781

Intra-cohort edges

A	B	Sources
FAN1	MTMR10	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FAN1	Q9Y2M0	18

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MTMR10	Q9NXD2	79.94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Synthesis of PIPs at the early endosome membrane	1	356.9×	0.014	MTMR10
PI Metabolism	1	178.4×	0.014	MTMR10
Fanconi Anemia Pathway	1	139.3×	0.014	FAN1
Phospholipid metabolism	1	100.2×	0.015	MTMR10
Metabolism of lipids	1	15.8×	0.075	MTMR10
Metabolism	1	5.8×	0.165	MTMR10

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
interstrand cross-link repair	1	432.1×	0.005	FAN1
nucleotide-excision repair	1	383.0×	0.005	FAN1
double-strand break repair via homologous recombination	1	156.0×	0.009	FAN1
DNA repair	1	63.8×	0.016	FAN1

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
FAN1	0	0
MTMR10	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	1	MTMR10
E	Difficult family or no structure, no drug	1	FAN1

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)
FAN1	0	—
MTMR10	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.