Is MEFV p.Ala448= (c.1344A>C) pathogenic?

MEFV p.Ala448= (c.1344A>C) is classified Conflicting classifications of pathogenicity in MEFV (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-26). Rare (popmax 0.104%, afr); Associated with familial Mediterranean fever.

What condition is associated with MEFV p.Ala448= (c.1344A>C)?

MEFV p.Ala448= (c.1344A>C) is associated with familial Mediterranean fever, familial Mediterranean fever, autosomal dominant, sweet syndrome (ClinVar).

How common is MEFV p.Ala448= (c.1344A>C) in the general population?

MEFV p.Ala448= (c.1344A>C) is rare (popmax 0.104%, afr) (gnomAD).

How is Familial Mediterranean fever inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

MEFV p.Ala448=

c.1344A>C · rs143337771 · VCV761100

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.104%, afr)

Conditions

familial Mediterranean fever

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.9	GERP -4
Overall
CADD	0.741	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.104% African / African-American · 78/75,052 alleles

Filtering AF 0.0853% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0785%

Overall 0.0057% 92/1,614,140 alleles · rare exomes 42/1,461,794 · genomes 50/152,346 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.104%	962
Admixed American	0.01%	10,003
Remaining individualsnot grpmax-eligible	0.008%	12,502
South Asian	0.00329%	30,361

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.Ala448=
Coding: c.1344A>C
MANE Select: NM_000243
dbSNP: rs143337771
Type: single nucleotide variant
Location: chr16:3248921 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.64 · 11 PDB
Residue 448: 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

familial Mediterranean fever — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial Mediterranean fever, autosomal dominant sweet syndrome

For Familial Mediterranean fever (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: >1 / 1000 (Turkey)

Similar variants

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
MEFV p.Ala768Gly 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-ala448 (accessed [today's date]).

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