Is MEFV p.Ser331Phe (c.992C>T) pathogenic?

MEFV p.Ser331Phe (c.992C>T) is classified Uncertain significance in MEFV (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-19). AlphaMissense: likely benign (0.1159); Very rare (popmax 0.000678%, nfe); Associated with Inborn genetic diseases.

What condition is associated with MEFV p.Ser331Phe (c.992C>T)?

MEFV p.Ser331Phe (c.992C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MEFV p.Ser331Phe (c.992C>T) in the general population?

MEFV p.Ser331Phe (c.992C>T) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about MEFV p.Ser331Phe (c.992C>T)?

AlphaMissense predicts likely benign (score 0.1159) — an in-silico prediction, not a clinical call.

MEFV p.Ser331Phe

c.992C>T · rs1959002659 · VCV870680

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1159 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1159	likely benign
REVEL	0.198	benign-leaning
SaProt	LLR -8.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.1	GERP 0.06, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 13 kb · p 2.1e-07 · regional, not allelic
Overall
CADD	21.4	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 0.000678% European (non-Finnish) · 8/1,179,688 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,613,708 alleles · very rare exomes 8/1,461,352 · genomes 0/152,356 · 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.Ser331Phe
Coding: c.992C>T
MANE Select: NM_000243
dbSNP: rs1959002659
Type: single nucleotide variant
Location: chr16:3249699 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.64 · 11 PDB
Residue 331: a functional site (cleavage; by casp1)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MEFV p.Cys332Tyr Uncertain significance ★★ ⚠ same condition
MEFV p.Gly137Ser Uncertain significance ★★ ⚠ same condition
MEFV p.Ala457= Likely benign ★★ same condition
MEFV p.Ala497= Likely benign ★★ same condition
MEFV p.Gln476= Benign/Likely benign ★★ same condition
MEFV p.Gln753= Likely benign ★★ same condition
MEFV p.Tyr60= Benign/Likely benign ★★ same condition
MEFV p.Ala199Gly 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-ser331phe (accessed [today's date]).

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