Is MEFV p.Pro335= (c.1005C>T) pathogenic?

MEFV p.Pro335= (c.1005C>T) is classified Conflicting classifications of pathogenicity in MEFV (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-22). Rare (popmax 0.12%, eas); Associated with familial Mediterranean fever, autosomal dominant.

What condition is associated with MEFV p.Pro335= (c.1005C>T)?

MEFV p.Pro335= (c.1005C>T) is associated with familial Mediterranean fever, autosomal dominant, sweet syndrome, familial Mediterranean fever (ClinVar).

How common is MEFV p.Pro335= (c.1005C>T) in the general population?

MEFV p.Pro335= (c.1005C>T) is rare (popmax 0.12%, eas) (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.Pro335=

c.1005C>T · rs567739580 · VCV1146940

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.12%, eas)

Conditions

familial Mediterranean fever, autosomal dominant

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 -1.8	GERP -3.8, phastCons 0.017
Overall
CADD	2.583	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.12% East Asian · 54/44,856 alleles

Filtering AF 0.0947% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0855%

Overall 0.0036% 58/1,612,942 alleles · rare exomes 55/1,460,612 · genomes 3/152,330 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.12%	831
Admixed American	0.00167%	59,954
Remaining individualsnot grpmax-eligible	0.0016%	62,462
South Asian	0.0011%	91,004
European (non-Finnish)	8.48e-05%	1,179,154

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.Pro335=
Coding: c.1005C>T
MANE Select: NM_000243
dbSNP: rs567739580
Type: single nucleotide variant
Location: chr16:3249686 (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

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

Also linked: sweet syndrome familial Mediterranean fever

For Familial Mediterranean fever (Orphanet):

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

Similar variants

MEFV p.Pro335His 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-pro335 (accessed [today's date]).

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