Is MEFV p.Ile423Ser (c.1268T>G) pathogenic?

MEFV p.Ile423Ser (c.1268T>G) is classified Uncertain significance in MEFV (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-27). AlphaMissense: likely pathogenic (0.7856); Very rare (popmax 0.000593%, nfe); Associated with familial Mediterranean fever.

What condition is associated with MEFV p.Ile423Ser (c.1268T>G)?

MEFV p.Ile423Ser (c.1268T>G) is associated with familial Mediterranean fever (ClinVar).

How common is MEFV p.Ile423Ser (c.1268T>G) in the general population?

MEFV p.Ile423Ser (c.1268T>G) is very rare (popmax 0.000593%, 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.Ile423Ser (c.1268T>G)?

AlphaMissense predicts likely pathogenic (score 0.7856) — an in-silico prediction, not a clinical call.

MEFV p.Ile423Ser

c.1268T>G · rs751508536 · VCV2145083

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7856 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

familial Mediterranean fever

Computational evidence

Protein change
AlphaMissense	0.7856	likely pathogenic · top 6% in MEFV
REVEL	0.389	indeterminate
SaProt	LLR -11.23	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9	GERP 0.98, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 13 kb · p 2.1e-07 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000593% European (non-Finnish) · 7/1,179,986 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000496% 8/1,613,990 alleles · very rare exomes 8/1,461,824 · genomes 0/152,166 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)grpmax	0.000593%	168,570

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile423Ser
Coding: c.1268T>G
MANE Select: NM_000243
dbSNP: rs751508536
Type: single nucleotide variant
Location: chr16:3248997 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.64 · 11 PDB
Residue 423: 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

familial Mediterranean fever — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial Mediterranean fever (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: >1 / 1000 (Turkey)

Similar variants

MEFV p.Ile423Val Uncertain significance ★ 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-ile423ser (accessed [today's date]).

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