Is MEFV p.Pro369Ser (c.1105C>T) pathogenic?

MEFV p.Pro369Ser (c.1105C>T) is classified Conflicting classifications of pathogenicity in MEFV (ClinVar, Conflicting submitters, 22 submitters; last evaluated 2026-02-11). AlphaMissense: likely benign (0.0908); Common (popmax 6.34%, eas) — too common for a highly-penetrant pathogenic allele; Associated with autoinflammatory syndrome.

What condition is associated with MEFV p.Pro369Ser (c.1105C>T)?

MEFV p.Pro369Ser (c.1105C>T) is associated with autoinflammatory syndrome, familial Mediterranean fever (ClinVar).

What do computational predictors say about MEFV p.Pro369Ser (c.1105C>T)?

AlphaMissense predicts likely benign (score 0.0908) — an in-silico prediction, not a clinical call.

MEFV p.Pro369Ser

Q: How common is MEFV p.Pro369Ser (c.1105C>T) in the general population?

MEFV p.Pro369Ser (c.1105C>T) is common (popmax 6.34%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1105C>T · rs11466023 · VCV2551

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 22 submitters

AlphaMissense

likely benign

0.0908 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.34%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.0908	likely benign
REVEL	0.242	benign-leaning
SaProt	LLR -6.08	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 1.3	GERP -0.97, phastCons 0.9
Regional constraint	o/e 1.16	unconstrained · MANE · 13 kb · p 2.1e-07 · regional, not allelic
Overall
CADD	19.64	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 6.34% East Asian · 2,844/44,866 alleles

Filtering AF 6.14% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.07%

Overall 1.05% 16,966/1,614,188 alleles · common exomes 15,105/1,461,866 · genomes 1,861/152,322 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	6.34%	16
Ashkenazi Jewishnot grpmax-eligible	3.06%	33
Amishnot grpmax-eligible	2.74%	36
Remaining individualsnot grpmax-eligible	1.78%	56
South Asian	1.57%	64
Middle Eastern	1.4%	71
Finnishnot grpmax-eligible	1.37%	73
Admixed American	0.833%	120
European (non-Finnish)	0.751%	133
African / African-American	0.437%	229

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.Pro369Ser
Coding: c.1105C>T
MANE Select: NM_000243
dbSNP: rs11466023
Type: single nucleotide variant
Location: chr16:3249586 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.64 · 11 PDB
Residue 369: a UniProt-annotated variant site (in arfmf; uncertain significance); the 'disordered' 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

Similar variants

MEFV p.Pro369Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
MEFV p.Pro369= Likely benign ★ 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

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-pro369ser (accessed [today's date]).

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