Is MEFV p.Arg348His (c.1043G>A) pathogenic?

MEFV p.Arg348His (c.1043G>A) is classified Conflicting classifications of pathogenicity in MEFV (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2023-07-26). AlphaMissense: likely benign (0.0718); Ultra-rare (popmax 0.0495%, mid); Associated with autoinflammatory syndrome.

What condition is associated with MEFV p.Arg348His (c.1043G>A)?

MEFV p.Arg348His (c.1043G>A) is associated with autoinflammatory syndrome, familial Mediterranean fever, autosomal dominant, sweet syndrome (ClinVar).

How common is MEFV p.Arg348His (c.1043G>A) in the general population?

MEFV p.Arg348His (c.1043G>A) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about MEFV p.Arg348His (c.1043G>A)?

AlphaMissense predicts likely benign (score 0.0718) — an in-silico prediction, not a clinical call.

MEFV p.Arg348His

c.1043G>A · rs104895198 · VCV97428

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.0718 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.0718	likely benign
REVEL	0.153	moderately benign-leaning
SaProt	LLR -7.41	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 -4.8	GERP -4.1
Regional constraint	o/e 1.16	unconstrained · MANE · 13 kb · p 2.1e-07 · regional, not allelic
Overall
CADD	0.138	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 0.0495% Middle Eastern · 3/6,060 alleles

Filtering AF 0.0322% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0285%

Overall 0.0193% 312/1,613,552 alleles · ultra-rare exomes 295/1,461,288 · genomes 17/152,264 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,020
South Asian	0.0429%	2,333
European (non-Finnish)	0.0209%	4,796
Remaining individualsnot grpmax-eligible	0.0144%	6,941
Admixed American	0.01%	9,994
East Asian	0.00891%	11,219
African / African-American	0.00666%	15,004

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.Arg348His
Coding: c.1043G>A
MANE Select: NM_000243
dbSNP: rs104895198
Type: single nucleotide variant
Location: chr16:3249648 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 73.64 · 11 PDB
Residue 348: 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, autosomal dominant sweet syndrome familial Mediterranean fever

Similar variants

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
MEFV p.Ala744Thr 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-arg348his (accessed [today's date]).

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