# NM_000243.3(MEFV):c.99G>A (p.Val33=)

https://sugi.bio/variant/mefv-p-val33

## Summary

**MEFV p.Val33= (c.99G>A)** is classified **Conflicting classifications of pathogenicity** in MEFV (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-16). Very rare (popmax 0.00915%, nfe); Associated with autoinflammatory syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs767848974 · 3 submitters · 2 linked conditions · very rare (popmax 0.00915%, nfe)

## 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 3 submitters, and is linked to autoinflammatory syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 4 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [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.Val33= |
| Coding change (HGVS c.) | c.99G>A |
| MANE Select transcript | [NM_000243](https://www.ncbi.nlm.nih.gov/nuccore/NM_000243) |
| dbSNP | [rs767848974](https://www.ncbi.nlm.nih.gov/snp/rs767848974/) |
| Variant type | single nucleotide variant |
| Location | chr16:3256489-3256489 (GRCh38) |
| ClinVar | [VCV1101415](https://www.ncbi.nlm.nih.gov/clinvar/variation/1101415/) |

**All HGVS expressions:** `LRG_190:g.5139G>A`, `LRG_190t1:c.99G>A`, `NC_000016.10:g.3256489C>T`, `NC_000016.9:g.3306489C>T`, `NG_007871.1:g.5139G>A`, `NM_000243.3:c.99G>A`, `NM_001198536.2:c.99G>A`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.263, GERP -2.47, phastCons 1 — weakly conserved position
- CADD: **PHRED 8.497**. 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.*
- 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 **0.00915%** (nfe) · FAF95 0.00774% · FAF99 0.00719% · 108/1,180,058 in the highest group · 108/1,614,098 alleles overall — very rare (popmax 0.00915%, nfe).

*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 **33** lies in the pyrin domain; a UniProt-annotated variant site (in); an α-helix.

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.Val33= falls in the pyrin domain. 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 2025-12-16.

**Submitter consensus:** conflicting (2 Likely benign, 1 Uncertain significance).

**Submission history:** 3 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-01-21 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2023-03-21 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-16 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Autoinflammatory syndrome, Familial Mediterranean fever, MEFV-related disorder, POLYSEROSITIS, FAMILIAL PAROXYSMAL, POLYSEROSITIS, RECURRENT, Periodic peritonitis, Benign paroxysmal peritonitis, MEFV-related condition, MEFV-related disorders.

## Similar variants {#similar}

Related MEFV variant pages (same residue, condition, or type): [MEFV p.Val33Leu](/variant/mefv-p-val33leu), [MEFV p.Val33Gly](/variant/mefv-p-val33gly), [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 1101415). 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.*