Is MEFV p.Pro147Ala (c.439C>G) pathogenic?

MEFV p.Pro147Ala (c.439C>G) is classified Conflicting classifications of pathogenicity in MEFV (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-02-08). AlphaMissense: likely benign (0.0706); Very rare (popmax 0.00051%, nfe); Associated with familial Mediterranean fever, autosomal dominant.

What condition is associated with MEFV p.Pro147Ala (c.439C>G)?

MEFV p.Pro147Ala (c.439C>G) is associated with familial Mediterranean fever, autosomal dominant, sweet syndrome, familial Mediterranean fever (ClinVar).

How common is MEFV p.Pro147Ala (c.439C>G) in the general population?

MEFV p.Pro147Ala (c.439C>G) is very rare (popmax 0.00051%, nfe) (gnomAD).

How is Familial Mediterranean fever inherited?

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

What do computational predictors say about MEFV p.Pro147Ala (c.439C>G)?

AlphaMissense predicts likely benign (score 0.0706) — an in-silico prediction, not a clinical call.

MEFV p.Pro147Ala

c.439C>G · rs876660991 · VCV234353

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0706 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00051%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial Mediterranean fever, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.0706	likely benign
REVEL	0.053	moderately benign-leaning
SaProt	LLR -6.18	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 -0.24	GERP -0.55
Regional constraint	o/e 1.16	unconstrained · MANE · 13 kb · p 2.1e-07 · regional, not allelic
Overall
CADD	3.625	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00051% European (non-Finnish) · 6/1,177,554 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000374% 6/1,605,364 alleles · very rare exomes 5/1,453,136 · genomes 1/152,228 · 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.Pro147Ala
Coding: c.439C>G
MANE Select: NM_000243
dbSNP: rs876660991
Type: single nucleotide variant
Location: chr16:3254629 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.64 · 11 PDB
Residue 147: the 'disordered' region

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.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-pro147ala (accessed [today's date]).

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