# NM_000243.3(MEFV):c.992C>T (p.Ser331Phe)

https://sugi.bio/variant/mefv-p-ser331phe

## Summary

**MEFV p.Ser331Phe (c.992C>T)** is classified **Uncertain significance** in MEFV (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-19). AlphaMissense: likely benign (0.1159); Very rare (popmax 0.000678%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1959002659 · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.000678%, nfe)

## For patients & families {#patients}

This is a change in the MEFV gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to Inborn genetic diseases.

*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.*

**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.Ser331Phe |
| Coding change (HGVS c.) | c.992C>T |
| MANE Select transcript | [NM_000243](https://www.ncbi.nlm.nih.gov/nuccore/NM_000243) |
| dbSNP | [rs1959002659](https://www.ncbi.nlm.nih.gov/snp/rs1959002659/) |
| Variant type | single nucleotide variant |
| Location | chr16:3249699-3249699 (GRCh38) |
| ClinVar | [VCV870680](https://www.ncbi.nlm.nih.gov/clinvar/variation/870680/) |

**All HGVS expressions:** `LRG_190:g.11929C>T`, `LRG_190t1:c.992C>T`, `NC_000016.10:g.3249699G>A`, `NC_000016.9:g.3299699G>A`, `NG_007871.1:g.11929C>T`, `NM_000243.2:c.992C>T`, `NM_000243.3:c.992C>T`, `NM_001198536.2:c.359C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1159)
- REVEL 0.198 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.667 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 4.137, GERP 0.06, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.4**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.23 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000678%** (nfe) · FAF95 0.000292% · FAF99 0.000211% · 8/1,179,688 in the highest group · 8/1,613,708 alleles overall — very rare (popmax 0.000678%, 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 **331** lies in a functional site (cleavage; by casp1).

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. 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-05-19.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2019–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-19 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-07-01 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, none provided.

## Similar variants {#similar}

Related MEFV variant pages (same residue, condition, or type): [MEFV p.Cys332Tyr](/variant/mefv-p-cys332tyr), [MEFV p.Gly137Ser](/variant/mefv-p-gly137ser), [MEFV p.Ala457=](/variant/mefv-p-ala457), [MEFV p.Ala497=](/variant/mefv-p-ala497), [MEFV p.Gln476=](/variant/mefv-p-gln476), [MEFV p.Gln753=](/variant/mefv-p-gln753), [MEFV p.Tyr60=](/variant/mefv-p-tyr60), [MEFV p.Ala199Gly](/variant/mefv-p-ala199gly).

### 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 870680). 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.*