Is MEFV p.Glu22= (c.66G>A) pathogenic?

MEFV p.Glu22= (c.66G>A) is classified Conflicting classifications of pathogenicity in MEFV (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-09). Ultra-rare (popmax 0.0516%, sas); Associated with Inborn genetic diseases.

What condition is associated with MEFV p.Glu22= (c.66G>A)?

MEFV p.Glu22= (c.66G>A) is associated with Inborn genetic diseases, familial Mediterranean fever (ClinVar).

How common is MEFV p.Glu22= (c.66G>A) in the general population?

MEFV p.Glu22= (c.66G>A) is ultra-rare (popmax 0.0516%, sas) (gnomAD).

MEFV p.Glu22=

c.66G>A · rs569040282 · VCV319119

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0516%, sas)

Conditions

Inborn genetic diseases

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 0.074	GERP -1.1, phastCons 0.9
Overall
CADD	8.788	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0516% South Asian · 47/91,086 alleles

Filtering AF 0.0398% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0357%

Overall 0.00359% 58/1,614,214 alleles · ultra-rare exomes 55/1,461,892 · genomes 3/152,322 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0516%	1,938
Remaining individualsnot grpmax-eligible	0.0112%	8,930
African / African-American	0.004%	25,018
European (non-Finnish)	8.47e-05%	1,180,045

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.Glu22=
Coding: c.66G>A
MANE Select: NM_000243
dbSNP: rs569040282
Type: single nucleotide variant
Location: chr16:3256522 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.64 · 11 PDB
Residue 22: the pyrin domain; an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial Mediterranean fever

Similar variants

MEFV p.Glu22Lys Uncertain significance ★★ ⚠ same residue
MEFV p.Glu22fs 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

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-glu22 (accessed [today's date]).

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