Is MEFV p.Pro50Ala (c.148C>G) pathogenic?

MEFV p.Pro50Ala (c.148C>G) is classified Uncertain significance in MEFV (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-21). AlphaMissense: likely benign (0.3368); Very rare (popmax 0.00333%, amr).

How common is MEFV p.Pro50Ala (c.148C>G) in the general population?

MEFV p.Pro50Ala (c.148C>G) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about MEFV p.Pro50Ala (c.148C>G)?

AlphaMissense predicts likely benign (score 0.3368) — an in-silico prediction, not a clinical call.

MEFV p.Pro50Ala

c.148C>G · rs1243710109 · VCV2689420

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3368 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3368	likely benign
REVEL	0.175	moderately benign-leaning
SaProt	LLR -8.55	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.6	GERP 2.1, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 13 kb · p 2.1e-07 · regional, not allelic
Overall
CADD	23.4	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

Grpmax group 0.00333% Admixed American · 2/60,028 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,614,238 alleles · very rare exomes 2/1,461,886 · genomes 0/152,352 · 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.Pro50Ala
Coding: c.148C>G
MANE Select: NM_000243
dbSNP: rs1243710109
Type: single nucleotide variant
Location: chr16:3256440 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.64 · 11 PDB
Residue 50: the pyrin domain; a turn

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

Similar variants

MEFV p.Pro50= Conflicting classifications of pathogenicity ★ same residue
MEFV p.Pro50Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MEFV p.Pro50Thr Uncertain significance ★ ⚠ same residue
MEFV p.Arg761His Pathogenic/Likely pathogenic ★★ ⚠ same type
MEFV p.Ser242Arg Pathogenic/Likely pathogenic ★★ same type
MEFV p.Val726Ala Pathogenic/Likely pathogenic ★★ ⚠ same type
MEFV c.*845C>T Uncertain significance ★★ same type
MEFV p.Ala193Thr Uncertain significance ★★ ⚠ same type

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-pro50ala (accessed [today's date]).

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