Is MEFV p.Ile506= (c.1518C>T) pathogenic?

MEFV p.Ile506= (c.1518C>T) is classified Conflicting classifications of pathogenicity in MEFV (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2026-01-26). Rare (popmax 0.396%, mid); Associated with autoinflammatory syndrome.

What condition is associated with MEFV p.Ile506= (c.1518C>T)?

MEFV p.Ile506= (c.1518C>T) is associated with autoinflammatory syndrome, familial Mediterranean fever (ClinVar).

How common is MEFV p.Ile506= (c.1518C>T) in the general population?

MEFV p.Ile506= (c.1518C>T) is rare (popmax 0.396%, mid) (gnomAD).

MEFV p.Ile506=

c.1518C>T · rs104895099 · VCV36502

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 14 submitters

gnomAD v4.1

Rare

rare (popmax 0.396%, mid)

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -0.063
Overall
CADD	0.558	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.396% Middle Eastern · 24/6,062 alleles

Filtering AF 0.273% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.232%

Overall 0.0136% 219/1,614,178 alleles · rare exomes 195/1,461,844 · genomes 24/152,334 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.396%	253
Remaining individualsnot grpmax-eligible	0.0272%	3,677
South Asian	0.0198%	5,059
African / African-American	0.0187%	5,360
European (non-Finnish)	0.0119%	8,429
Admixed American	0.005%	20,005
East Asian	0.00446%	22,442
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MEFV
Protein: p.Ile506=
Coding: c.1518C>T
MANE Select: NM_000243
dbSNP: rs104895099
Type: single nucleotide variant
Location: chr16:3247085 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.64 · 11 PDB
Residue 506: an α-helix; the 'required for homotrimerization and induction of pyroptosomes' region

Full MEFV gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autoinflammatory syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial Mediterranean fever

Similar variants

MEFV p.Ile506Val Uncertain significance ★ ⚠ same residue
MEFV p.Arg761His Pathogenic/Likely pathogenic ★★ ⚠ same condition
MEFV p.Ser242Arg Pathogenic/Likely pathogenic ★★ same condition
MEFV p.Val726Ala Pathogenic/Likely pathogenic ★★ ⚠ same condition
MEFV c.*845C>T Uncertain significance ★★ same condition
MEFV p.Ala193Thr Uncertain significance ★★ ⚠ same condition
MEFV p.Ala2Gly Uncertain significance ★★ ⚠ same condition
MEFV p.Ala416Thr Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mefv-p-ile506 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown