MEFV

Chr 16ADAR

MEFV innate immunity regulator, pyrin

NCBI Gene: 4210ENSG00000103313UniProt: O15553

Involved in the regulation of innate immunity and the inflammatory response in response to IFNG/IFN-gamma (PubMed:10807793, PubMed:11468188, PubMed:16037825, PubMed:16785446, PubMed:17431422, PubMed:17964261, PubMed:18577712, PubMed:19109554, PubMed:19584923, PubMed:26347139, PubMed:27030597, PubMed:28835462). Organizes autophagic machinery by serving as a platform for the assembly of ULK1, Beclin 1/BECN1, ATG16L1, and ATG8 family members and recognizes specific autophagy targets, thus coordinating target recognition with assembly of the autophagic apparatus and initiation of autophagy (PubMed:16785446, PubMed:17431422, PubMed:26347139). Acts as an autophagy receptor for the degradation of several inflammasome components, including CASP1, NLRP1 and NLRP3, hence preventing excessive IL1B- and IL18-mediated inflammation (PubMed:16785446, PubMed:17431422, PubMed:26347139). However, it can also have a positive effect in the inflammatory pathway, acting as an innate immune sensor that triggers PYCARD/ASC specks formation, caspase-1 activation, and IL1B and IL18 production (PubMed:16037825, PubMed:27030597, PubMed:28835462). Together with AIM2, also acts as a mediator of pyroptosis, necroptosis and apoptosis (PANoptosis), an integral part of host defense against pathogens, in response to bacterial infection (By similarity). It is required for PSTPIP1-induced PYCARD/ASC oligomerization and inflammasome formation (PubMed:10807793, PubMed:11468188, PubMed:17964261, PubMed:18577712, PubMed:19109554, PubMed:19584923). Recruits PSTPIP1 to inflammasomes, and is required for PSTPIP1 oligomerization (PubMed:10807793, PubMed:11468188, PubMed:17964261, PubMed:18577712, PubMed:19109554, PubMed:19584923)

Primary Disease Associations & Inheritance

Familial Mediterranean fever, ADMIM #134610
AD
Familial Mediterranean fever, ARMIM #249100
AR
Neutrophilic dermatosis, acute febrileMIM #608068
AD
UniProtPyrin-associated autoinflammatory disease
698
ClinVar variants
13
Pathogenic / LP
0.00
pLI score
4
Active trials
Clinical Summary— MEFV
🧬
Gene-Disease Validity (ClinGen)
familial Mediterranean fever · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
13 Pathogenic / Likely Pathogenic· 310 VUS of 698 total submissions
💊
Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.13LOEUF
pLI 0.000
Z-score 0.99
OE 0.81 (0.59–1.13)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-1.72Z-score
OE missense 1.23 (1.14–1.32)
551 obs / 448.7 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.81 (0.59–1.13)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.23 (1.14–1.32)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.23
0≤1.21.6
LoF obs/exp: 25 / 30.9Missense obs/exp: 551 / 448.7Syn Z: -2.50

ClinVar Variant Classifications

698 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9
Likely Pathogenic4
VUS310
Likely Benign327
Benign8
Conflicting40
9
Pathogenic
4
Likely Pathogenic
310
VUS
327
Likely Benign
8
Benign
40
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
9
0
9
Likely Pathogenic
2
0
2
0
4
VUS
18
251
40
1
310
Likely Benign
1
12
95
219
327
Benign
0
0
7
1
8
Conflicting
—40
Total21263153221698

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

MEFV · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

MEFV-related familial mediterranean fever

definitive
ARLoss Of FunctionAbsent Gene Product
Skin
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Familial Mediterranean fever, AD

MIM #134610

Molecular basis of disorder known

Autosomal dominant

Familial Mediterranean fever, AR

MIM #249100

Molecular basis of disorder known

Autosomal recessive

Neutrophilic dermatosis, acute febrile

MIM #608068

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — MEFV
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The grandfather's fever.
Ricci P et al.·Clin Rheumatol
2020Review
Involvement of Mediterranean fever gene mutations in colchicine-responsive enterocolitis: a retrospective cohort study.
Nakase H et al.·EBioMedicine
2024Cohort
Familial Mediterranean fever.
Bakkaloglu A·Pediatr Nephrol
2003Review
Clinical features and novel pathogenic variants of patients with Behçet's disease like trisomy 8.
Ding X et al.·Orphanet J Rare Dis
2025Cohort
Update in familial Mediterranean fever.
Ozen S·Curr Opin Rheumatol
2021Review
The Impact of Different MEFV Genotypes on Clinical Phenotype of Patients with Familial Mediterranean Fever: Special Emphasis on Joint Involvement.
Aslan E et al.·Eur J Pediatr
2024Cohort
Clinical Associations of E148Q Heterozygosity: What to Expect From E148Q?
Küçükali B et al.·J Clin Rheumatol
2024
Background and Clinical Features of a Unique and Mysterious Autoinflammatory Disease, Schnitzler Syndrome.
Műzes G et al.·Int J Mol Sci
2025Review
Exploring factors for predicting colchicine responsiveness in children with PFAPA.
Özaslan Z et al.·Eur J Pediatr
2024
Functional Assessment of Disease-Associated Pyrin Variants.
Chirita D et al.·Methods Mol Biol
2022Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Large-vessel vasculitis in Behçet's disease carrying MEFV exon 10 variants: a case suggesting a pyrin-associated autoinflammatory background.
Nishimura N et al.·Mod Rheumatol Case Rep
2026
The clinical significance of the Mediterranean fever gene MEFV variants in Castleman disease.
Du Y et al.·Commun Med (Lond)
2026🔓 Open Access
Impact of MEFV gene variants on clinical presentation in Familial Mediterranean Fever: A focus on Exon 2 mutations.
Kulaksiz B et al.·Reumatol Clin (Engl Ed)
2026
Nephrotic syndrome genomic discovery in the Mass General Brigham Biobank identifies monoallelic MEFV variants as a risk factor for focal segmental glomerulosclerosis.
Wongboonsin J et al.·Kidney Int
2025
The Role of NLRP1, AIM2 and MEFV Inflammasomes in the High-Intensity Interval Training of Individuals With Obesity.
Silveira ALPA et al.·Immunology
2025
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Familial Mediterranean Fever

Health-related Quality of Life, Electrocardiographic and Holter Findings in Children With Familial Mediterranean Fever

ACTIVE NOT RECRUITING
NCT07128225Sohag UniversityStarted 2025-03-01
Familial Mediterranean Fever (FMF)AutoinflammationPeriodic Fever

Familial Mediterranean Fever and Related Disorders: Genetics and Disease Characteristics

RECRUITING
NCT00001373National Human Genome Research Institute (NHGRI)Started 1994-03-10
Familial Mediterranean FeverMEFV Gene Mutation

Characterization of a Functional Test for Mediterranean Family Fever Screening - 2

RECRUITING
NCT04478409Hospices Civils de LyonStarted 2021-07-21
one additional blood sample during a planned blood test
Familial Mediterranean FeverNon-celiac Gluten Sensitivity

Can Gluten/Wheat or Other Foods be Responsible for FMF Attacks

RECRUITING
NCT06338891University of PalermoStarted 2024-05-01
Main questionnaireSecondary questionnaire

External Resources

Links to major genomics databases and tools