# NM_000243.3(MEFV):c.344C>G (p.Pro115Arg)

https://sugi.bio/variant/mefv-p-pro115arg

## Summary

**MEFV p.Pro115Arg (c.344C>G)** is classified **Conflicting classifications of pathogenicity** in MEFV (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-27). AlphaMissense: likely benign (0.0861); Rare (popmax 0.25%, eas); Associated with familial Mediterranean fever.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs201766654 · 4 submitters · 1 linked condition · AlphaMissense likely benign · rare (popmax 0.25%, eas)

## For patients & families {#patients}

This is a change in the MEFV gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to familial Mediterranean fever.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy |
| Prevalence | >1 / 1000 (Turkey) |
| Clinical trials | 61 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | MEFV is a diagnostic-grade gene on 6 Genomics England panels |

**Commonly reported features of Familial Mediterranean fever** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Constipation — Very frequent (99-80%)
- Abdominal pain — Very frequent (99-80%)
- Arthralgia — Very frequent (99-80%)
- Myalgia — Very frequent (99-80%)
- Fever — Very frequent (99-80%)
- Nausea and vomiting — Very frequent (99-80%)
- Proteinuria — Frequent (79-30%)
- Irritability — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006421/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MEFV](https://sugi.bio/atlas/gene/MEFV/) |
| Protein change (HGVS p.) | p.Pro115Arg |
| Coding change (HGVS c.) | c.344C>G |
| MANE Select transcript | [NM_000243](https://www.ncbi.nlm.nih.gov/nuccore/NM_000243) |
| dbSNP | [rs201766654](https://www.ncbi.nlm.nih.gov/snp/rs201766654/) |
| Variant type | single nucleotide variant |
| Location | chr16:3254724-3254724 (GRCh38) |
| ClinVar | [VCV763253](https://www.ncbi.nlm.nih.gov/clinvar/variation/763253/) |

**All HGVS expressions:** `LRG_190:g.6904C>G`, `LRG_190t1:c.344C>G`, `NC_000016.10:g.3254724G>C`, `NC_000016.9:g.3304724G>C`, `NG_007871.1:g.6904C>G`, `NM_000243.3:c.344C>G`, `NM_001198536.2:c.277+1587C>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.0861)
- REVEL 0.27 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.616 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.434, GERP -4.07, phastCons 0.469 — weakly conserved position
- CADD: **PHRED 11.14**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 1.16** across the covering region of the MANE Select transcript (3,243,144–3,256,587), spanning 13,443 bp. Chi-square p 2.1e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.25%** (eas) · FAF95 0.212% · FAF99 0.198% · 112/44,886 in the highest group · 114/1,612,868 alleles overall — rare (popmax 0.25%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.25% | 401 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,246 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**MEFV** population constraint: LOEUF 1.147, pLI 2.305e-19, missense-Z -1.6136; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **familial Mediterranean fever** — Definitive (SD)

## Protein context {#protein}

Residue **115** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 73.64, 50% of residues very-high.

**11 experimental structure(s)** (PDB): [2MPC](https://www.rcsb.org/structure/2MPC), [2WL1](https://www.rcsb.org/structure/2WL1), [4CG4](https://www.rcsb.org/structure/4CG4), [8C28](https://www.rcsb.org/structure/8C28), [8C2Y](https://www.rcsb.org/structure/8C2Y), [8C30](https://www.rcsb.org/structure/8C30).

## What this gene does {#gene-function}

*Describes the biological roles of MEFV (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** MEFV's established molecular role includes actin binding. p.Pro115Arg falls in the disordered region. In Reactome, MEFV is annotated in disease pathway(s) including **Purinergic signaling in leishmaniasis infection**.

**Disease mechanism (Reactome):** MEFV loss or alteration is curated in [Purinergic signaling in leishmaniasis infection](https://reactome.org/content/detail/R-HSA-9660826).

### Pathways affected {#pathways}

MEFV participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Purinergic signaling in leishmaniasis infection](https://reactome.org/content/detail/R-HSA-9660826) | curated |
| [The NLRP3 inflammasome](https://reactome.org/content/detail/R-HSA-844456) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** actin binding, identical protein binding.

**Biological process:** inflammatory response, positive regulation of autophagy, regulation of interleukin-1 beta production, negative regulation of interleukin-1 beta production, negative regulation of interleukin-12 production, positive regulation of interleukin-1 beta production.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-11-27.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 Likely benign).

**Submission history:** 4 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-04-27 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-08-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-27 |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-02 |

## Associated conditions {#conditions}

[familial Mediterranean fever](https://sugi.bio/atlas/disease/familial-mediterranean-fever/).

**Reported phenotype names (ClinVar):** Familial Mediterranean fever, not provided, POLYSEROSITIS, FAMILIAL PAROXYSMAL, POLYSEROSITIS, RECURRENT, Periodic peritonitis, Benign paroxysmal peritonitis, none provided.

## Similar variants {#similar}

Related MEFV variant pages (same residue, condition, or type): [MEFV p.Pro115Ser](/variant/mefv-p-pro115ser), [MEFV p.Pro115Thr](/variant/mefv-p-pro115thr), [MEFV p.Arg761His](/variant/mefv-p-arg761his), [MEFV p.Ser242Arg](/variant/mefv-p-ser242arg), [MEFV p.Val726Ala](/variant/mefv-p-val726ala), [MEFV c.*845C>T](/variant/mefv-c-star-845c-t), [MEFV p.Ala193Thr](/variant/mefv-p-ala193thr), [MEFV p.Ala2Gly](/variant/mefv-p-ala2gly).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 763253). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*