Is MEFV p.Pro228Ser (c.682C>T) pathogenic?

MEFV p.Pro228Ser (c.682C>T) is classified Uncertain significance in MEFV (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-08). AlphaMissense: likely benign (0.0767); Absent from gnomAD v4.1; Associated with sweet syndrome.

What condition is associated with MEFV p.Pro228Ser (c.682C>T)?

MEFV p.Pro228Ser (c.682C>T) is associated with sweet syndrome, familial Mediterranean fever, autosomal dominant, familial Mediterranean fever (ClinVar).

How common is MEFV p.Pro228Ser (c.682C>T) in the general population?

MEFV p.Pro228Ser (c.682C>T) is absent from gnomAD v4.1 (gnomAD).

How is Sweet syndrome inherited?

Typically Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MEFV p.Pro228Ser (c.682C>T)?

AlphaMissense predicts likely benign (score 0.0767) — an in-silico prediction, not a clinical call.

MEFV p.Pro228Ser

c.682C>T · rs1596358139 · VCV647727

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0767 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

sweet syndrome

Computational evidence

Protein change
AlphaMissense	0.0767	likely benign
REVEL	0.075	moderately benign-leaning
SaProt	LLR -3.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.17	GERP -3.6
Regional constraint	o/e 1.16	unconstrained · MANE · 13 kb · p 2.1e-07 · regional, not allelic
Overall
CADD	0.046	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MEFV
Protein: p.Pro228Ser
Coding: c.682C>T
MANE Select: NM_000243
dbSNP: rs1596358139
Type: single nucleotide variant
Location: chr16:3254386 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.64 · 11 PDB

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

Disease context

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

Also linked: familial Mediterranean fever, autosomal dominant familial Mediterranean fever

For Sweet syndrome (Orphanet):

Inheritance: Multigenic/multifactorial
Onset: Adult

Similar variants

MEFV p.Pro228Leu 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-pro228ser (accessed [today's date]).

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