Is MEFV p.Ser503Cys (c.1508C>G) pathogenic?

MEFV p.Ser503Cys (c.1508C>G) is classified Conflicting classifications of pathogenicity in MEFV (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-01-13). AlphaMissense: likely benign (0.0996); Low-frequency (popmax 1.22%, eas); Associated with autoinflammatory syndrome.

What condition is associated with MEFV p.Ser503Cys (c.1508C>G)?

MEFV p.Ser503Cys (c.1508C>G) is associated with autoinflammatory syndrome, familial Mediterranean fever, autosomal dominant, sweet syndrome (ClinVar).

How common is MEFV p.Ser503Cys (c.1508C>G) in the general population?

MEFV p.Ser503Cys (c.1508C>G) is low-frequency (popmax 1.22%, eas) (gnomAD).

What do computational predictors say about MEFV p.Ser503Cys (c.1508C>G)?

AlphaMissense predicts likely benign (score 0.0996) — an in-silico prediction, not a clinical call.

MEFV p.Ser503Cys

c.1508C>G · rs190705322 · VCV457996

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0996 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.22%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.0996	likely benign
REVEL	0.346	indeterminate
SaProt	LLR -8.79	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 0.97, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 13 kb · p 2.1e-07 · regional, not allelic
Overall
CADD	19.0	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 1.22% East Asian · 548/44,882 alleles

Filtering AF 1.14% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1%

Overall 0.0346% 558/1,614,192 alleles · low-frequency exomes 548/1,461,840 · genomes 10/152,352 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	1.22%	82
Remaining individualsnot grpmax-eligible	0.0144%	6,946
European (non-Finnish)	8.47e-05%	1,180,022

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.Ser503Cys
Coding: c.1508C>G
MANE Select: NM_000243
dbSNP: rs190705322
Type: single nucleotide variant
Location: chr16:3247095 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.64 · 11 PDB
Residue 503: an α-helix; the 'required for homotrimerization and induction of pyroptosomes' region

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

Disease context

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

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

Similar variants

MEFV p.Ser503fs Likely pathogenic ★★ 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-ser503cys (accessed [today's date]).

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