Is MEFV p.Arg441Ter (c.1321C>T) pathogenic?

MEFV p.Arg441Ter (c.1321C>T) is classified Likely pathogenic in MEFV (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-01). Very rare (popmax 0.00119%, nfe); Associated with autoinflammatory syndrome.

What condition is associated with MEFV p.Arg441Ter (c.1321C>T)?

MEFV p.Arg441Ter (c.1321C>T) is associated with autoinflammatory syndrome (ClinVar).

How common is MEFV p.Arg441Ter (c.1321C>T) in the general population?

MEFV p.Arg441Ter (c.1321C>T) is very rare (popmax 0.00119%, nfe) (gnomAD).

MEFV p.Arg441Ter

c.1321C>T · rs768066753 · VCV1694332

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 10
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.34 · evaluated, not missing
Pangolin	Δ0.30	loss · gain 0.00 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 2.3	GERP -0.28, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00119% European (non-Finnish) · 14/1,180,024 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000867% 14/1,614,052 alleles · very rare exomes 13/1,461,854 · genomes 1/152,198 · joint denominator

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.Arg441Ter
Coding: c.1321C>T
MANE Select: NM_000243
dbSNP: rs768066753
Type: single nucleotide variant
Location: chr16:3248944 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.64 · 11 PDB
Residue 441: 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

Similar variants

MEFV p.Arg441Gln Uncertain significance ★★ ⚠ same residue
MEFV p.Arg761His Pathogenic/Likely pathogenic ★★ ⚠ same condition
MEFV p.Val726Ala Pathogenic/Likely pathogenic ★★ ⚠ same condition
MEFV p.Ala744Thr Uncertain significance ★★ ⚠ same condition
MEFV p.Arg80Cys Uncertain significance ★★ ⚠ same condition
MEFV p.Gly137Ser Uncertain significance ★★ ⚠ same condition
MEFV p.Gly196Arg Uncertain significance ★★ ⚠ same condition
MEFV p.Ser339Phe 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-arg441ter (accessed [today's date]).

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