familial Mediterranean fever, autosomal dominant

Summary

familial Mediterranean fever, autosomal dominant (MONDO:0007601) is a disease caused by MEFV (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: MEFV (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 344

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial Mediterranean fever, autosomal dominant
Mondo ID	MONDO:0007601
MeSH	C565021
OMIM	134610
UMLS	C1851347
MedGen	341987
GARD	0015069
Is cancer (heuristic)	no

Also known as: familial Mediterranean fever, AD · familial Mediterranean fever, autosomal dominant

Data availability: 344 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › familial Mediterranean fever › familial Mediterranean fever, autosomal dominant

Related subtypes (1): autosomal recessive familial Mediterranean fever

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

344 retrieved; paginated sample, class counts are floors:

205 conflicting classifications of pathogenicity, 101 uncertain significance, 15 benign, 11 benign/likely benign, 7 pathogenic/likely pathogenic, 3 pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2555	NM_000243.2(MEFV):c.[442G>C;2082G>A]		Pathogenic	no assertion criteria provided
2538	NM_000243.3(MEFV):c.2080A>G (p.Met694Val)	LOC126862264	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2539	NM_000243.3(MEFV):c.2082G>A (p.Met694Ile)	LOC126862264	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2550	NM_000243.3(MEFV):c.2040G>A (p.Met680Ile)	LOC126862264	Pathogenic	criteria provided, multiple submitters, no conflicts
2553	NM_000243.3(MEFV):c.1958G>A (p.Arg653His)	LOC126862264	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
36507	NM_000243.3(MEFV):c.2040G>C (p.Met680Ile)	LOC126862264	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179060	NM_000243.3(MEFV):c.1510C>T (p.Gln504Ter)	MEFV	Pathogenic	criteria provided, single submitter
2540	NM_000243.3(MEFV):c.2177T>C (p.Val726Ala)	MEFV	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2549	NM_000243.3(MEFV):c.2282G>A (p.Arg761His)	MEFV	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
97540	NM_000243.3(MEFV):c.726C>A (p.Ser242Arg)	MEFV	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179055	NM_000243.3(MEFV):c.1597_1598dup (p.Asp533fs)	MEFV	Likely pathogenic	criteria provided, single submitter
987917	NM_000243.2:c.(?911)(1356_?)del	MEFV	Likely pathogenic	criteria provided, single submitter
1062670	NM_000243.3(MEFV):c.1957C>A (p.Arg653Ser)	LOC126862264	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1467370	NM_000243.3(MEFV):c.1685A>G (p.Gln562Arg)	LOC126862264	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1478684	NM_000243.3(MEFV):c.2078T>C (p.Met693Thr)	LOC126862264	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234363	NM_000243.3(MEFV):c.1759+1G>A	LOC126862264	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234364	NM_000243.3(MEFV):c.1886dup (p.Pro630fs)	LOC126862264	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234366	NM_000243.3(MEFV):c.2146A>G (p.Lys716Glu)	LOC126862264	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234551	NM_000243.3(MEFV):c.2141C>T (p.Pro714Leu)	LOC126862264	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2547	NM_000243.3(MEFV):c.2084A>G (p.Lys695Arg)	LOC126862264	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2556	NM_000243.3(MEFV):c.2078TGA[1] (p.Met694del)	LOC126862264	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
289866	NM_000243.3(MEFV):c.1957C>T (p.Arg653Cys)	LOC126862264	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
36506	NM_000243.3(MEFV):c.1772T>C (p.Ile591Thr)	LOC126862264	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
36508	NM_000243.3(MEFV):c.2118G>A (p.Pro706=)	LOC126862264	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
439888	NM_000243.3(MEFV):c.1759+11C>T	LOC126862264	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
457998	NM_000243.3(MEFV):c.1898C>T (p.Pro633Leu)	LOC126862264	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
458000	NM_000243.3(MEFV):c.2163C>T (p.Phe721=)	LOC126862264	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
527802	NM_000243.3(MEFV):c.1780C>T (p.Gln594Ter)	LOC126862264	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
577934	NM_000243.3(MEFV):c.2044_2045del (p.Leu682fs)	LOC126862264	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
641743	NM_000243.3(MEFV):c.1735C>T (p.Arg579Cys)	LOC126862264	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 11 · 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
MEFV	Definitive	Autosomal recessive	familial Mediterranean fever	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MEFV	Orphanet:117	Behçet disease
MEFV	Orphanet:3243	Sweet syndrome
MEFV	Orphanet:329967	Intermittent hydrarthrosis
MEFV	Orphanet:342	Familial Mediterranean fever
MPL	Orphanet:3318	Essential thrombocythemia
MPL	Orphanet:3319	Congenital amegakaryocytic thrombocytopenia
MPL	Orphanet:397692	Hereditary isolated aplastic anemia
MPL	Orphanet:71493	Familial thrombocytosis
MPL	Orphanet:824	Primary myelofibrosis
MTM1	Orphanet:456328	X-linked myotubular myopathy-abnormal genitalia syndrome
MTM1	Orphanet:596	X-linked centronuclear myopathy

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MEFV	HGNC:6998	ENSG00000103313	O15553	Pyrin	gencc,clinvar
MPL	HGNC:7217	ENSG00000117400	P40238	Thrombopoietin receptor	clinvar
MTM1	HGNC:7448	ENSG00000171100	Q13496	Myotubularin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MEFV	Pyrin	Involved in the regulation of innate immunity and the inflammatory response in response to IFNG/IFN-gamma.
MPL	Thrombopoietin receptor	Receptor for thrombopoietin that regulates hematopoietic stem cell renewal, megakaryocyte differentiation, and platelet formation.
MTM1	Myotubularin	Lipid phosphatase which dephosphorylates phosphatidylinositol 3-monophosphate (PI3P) and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2).

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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	28.0×	0.106
Antibody/Immunoglobulin	1	9.7×	0.149
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MEFV	Transcription factor	no		Znf_B-box, B30.2/SPRY, SPRY_dom
MPL	Antibody/Immunoglobulin	yes		Long_hematopoietin_rcpt_CS, FN3_dom, Ig-like_fold
MTM1	Phosphatase	yes	3.1.3.64	Tyr_Pase_dom, Tyr_Pase_cat, GRAM

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
monocyte	2
mononuclear cell	2
buccal mucosa cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
germinal epithelium of ovary	1
rectum	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MEFV	153	broad	marker	buccal mucosa cell, monocyte, mononuclear cell
MPL	166	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, mononuclear cell, monocyte
MTM1	281	ubiquitous	marker	secondary oocyte, rectum, germinal epithelium of ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MEFV	2,217
MTM1	1,415
MPL	1,039

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MEFV	O15553	11
MPL	P40238	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MTM1	Q13496	90.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 3 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
Inflammasomes	1	380.7×	0.017	MEFV
Cell recruitment (pro-inflammatory response)	1	380.7×	0.017	MEFV
Synthesis of PIPs at the late endosome membrane	1	317.2×	0.017	MTM1
Synthesis of PIPs at the early endosome membrane	1	237.9×	0.017	MTM1
The NLRP3 inflammasome	1	223.9×	0.017	MEFV
Platelet Aggregation (Plug Formation)	1	146.4×	0.018	MPL
Purinergic signaling in leishmaniasis infection	1	141.0×	0.018	MEFV
PI Metabolism	1	119.0×	0.018	MTM1
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1	119.0×	0.018	MEFV
Synthesis of PIPs at the plasma membrane	1	70.5×	0.026	MTM1
Phospholipid metabolism	1	66.8×	0.026	MTM1
Leishmania infection	1	54.4×	0.027	MEFV
Parasitic Infection Pathways	1	54.4×	0.027	MEFV
Metabolism of lipids	1	10.5×	0.125	MTM1
Innate Immune System	1	8.5×	0.138	MEFV
Infectious disease	1	8.3×	0.138	MEFV
Disease	1	4.4×	0.226	MEFV
Immune System	1	4.3×	0.226	MEFV
Metabolism	1	3.9×	0.237	MTM1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of vacuole organization	1	5617.3×	0.004	MTM1
basophil homeostasis	1	5617.3×	0.004	MPL
pyroptosome complex assembly	1	2808.7×	0.004	MEFV
positive regulation of platelet formation	1	2808.7×	0.004	MPL
monocyte homeostasis	1	1872.4×	0.004	MPL
negative regulation of macrophage inflammatory protein 1 alpha production	1	1872.4×	0.004	MEFV
eosinophil homeostasis	1	1872.4×	0.004	MPL
positive regulation of skeletal muscle tissue growth	1	1123.5×	0.005	MTM1
skeletal muscle tissue growth	1	936.2×	0.005	MTM1
regulation of interleukin-1 beta production	1	702.2×	0.005	MEFV
thrombopoietin-mediated signaling pathway	1	702.2×	0.005	MPL
mitochondrion distribution	1	702.2×	0.005	MTM1
positive regulation of lymphocyte proliferation	1	624.1×	0.006	MPL
neutrophil homeostasis	1	510.7×	0.006	MPL
negative regulation of autophagosome assembly	1	432.1×	0.007	MTM1
negative regulation of interleukin-12 production	1	351.1×	0.008	MEFV
pattern recognition receptor signaling pathway	1	330.4×	0.008	MEFV
negative regulation of NLRP3 inflammasome complex assembly	1	330.4×	0.008	MEFV
TOR signaling	1	255.3×	0.009	MTM1
platelet formation	1	234.1×	0.010	MPL
muscle cell cellular homeostasis	1	216.1×	0.010	MTM1
phosphatidylinositol dephosphorylation	1	216.1×	0.010	MTM1
negative regulation of TOR signaling	1	187.2×	0.010	MTM1
response to type II interferon	1	175.5×	0.010	MEFV
negative regulation of interleukin-1 beta production	1	170.2×	0.010	MEFV
pyroptotic inflammatory response	1	170.2×	0.010	MEFV
negative regulation of cytokine production involved in inflammatory response	1	140.4×	0.012	MEFV
negative regulation of proteasomal ubiquitin-dependent protein catabolic process	1	133.8×	0.012	MTM1
phosphatidylinositol biosynthetic process	1	122.1×	0.013	MTM1
endosome to lysosome transport	1	112.3×	0.014	MTM1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
MPL	LUSUTROMBOPAG

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MPL	2	4
MEFV	0	0
MTM1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LUSUTROMBOPAG	4	MPL
ELTROMBOPAG	4	MPL

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MPL	23	Functional:15, Binding:7, ADMET:1
MEFV	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MTM1	3.1.3.64, 3.1.3.95	phosphatidylinositol-3-phosphatase, phosphatidylinositol-3,5-bisphosphate 3-phosphatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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)
LUSUTROMBOPAG	4	MPL
ELTROMBOPAG	4	MPL

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MPL
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	MTM1
E	Difficult family or no structure, no drug	1	MEFV

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)
MEFV	1	—
MTM1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.