# NM_000243.3(MEFV):c.986G>A (p.Arg329His)

https://sugi.bio/variant/mefv-p-arg329his

## Summary

**MEFV p.Arg329His (c.986G>A)** is classified **Conflicting classifications of pathogenicity** in MEFV (ClinVar, Conflicting submitters, 18 submitters; last evaluated 2026-03-01). AlphaMissense: likely benign (0.0673); Rare (popmax 0.249%, nfe); Associated with autoinflammatory syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs104895112 · 18 submitters · 4 linked conditions · AlphaMissense likely benign · rare (popmax 0.249%, 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 18 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.Arg329His |
| Coding change (HGVS c.) | c.986G>A |
| MANE Select transcript | [NM_000243](https://www.ncbi.nlm.nih.gov/nuccore/NM_000243) |
| dbSNP | [rs104895112](https://www.ncbi.nlm.nih.gov/snp/rs104895112/) |
| Variant type | single nucleotide variant |
| Location | chr16:3249705-3249705 (GRCh38) |
| ClinVar | [VCV97557](https://www.ncbi.nlm.nih.gov/clinvar/variation/97557/) |

**All HGVS expressions:** `LRG_190:g.11923G>A`, `LRG_190t1:c.986G>A`, `NC_000016.10:g.3249705C>T`, `NC_000016.9:g.3299705C>T`, `NG_007871.1:g.11923G>A`, `NM_000243.3:c.986G>A`, `NM_001198536.2:c.353G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0673)
- REVEL 0.166 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.804 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.877, GERP -4.38 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.37**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. This allele is not in the release, so all four of its deltas are under 0.2. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, and here that is proven rather than inferred: a different substitution at this very position, C>A, IS in the release and scores Δ0.52 acceptor gain, so SpliceAI evaluated this position and this allele was not among the ones that cleared the filter. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.249%** (nfe) · FAF95 0.241% · FAF99 0.238% · 2,934/1,179,790 in the highest group · 3,670/1,613,764 alleles overall — rare (popmax 0.249%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 1.17% | 86 |
| Remaining individuals (not grpmax-eligible) | 0.259% | 386 |
| European (non-Finnish) (grpmax) | 0.249% | 402 |
| South Asian | 0.181% | 552 |
| Middle Eastern | 0.0661% | 1,514 |
| Admixed American | 0.0433% | 2,308 |
| African / African-American | 0.036% | 2,780 |
| Finnish (not grpmax-eligible) | 0.0109% | 9,145 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. 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.

*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}


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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-03-01.

**Submitter consensus:** conflicting (10 Uncertain significance, 6 Likely benign, 3 not provided).

**Submission history:** 19 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Unité médicale des maladies autoinflammatoires, CHRU Montpellier | not provided | no classification provided | not provided |  |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-10-28 |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Likely benign | no assertion criteria provided | clinical testing |  |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-11 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-07-13 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-03-01 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-04-27 |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-05-04 |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-01-20 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-02-28 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-20 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-03 |
| Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-09-28 |
| Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-12-08 |
| Center for Personalized Medicine, Children's Hospital Los Angeles | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-11-19 |
| GenomeConnect, ClinGen | not provided | no classification provided | phenotyping only |  |
| GenomeConnect - Invitae Patient Insights Network | not provided | no classification provided | phenotyping only |  |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-14 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Autoinflammatory syndrome, Familial Mediterranean fever, not provided, not specified, Familial Mediterranean fever, autosomal dominant, Acute febrile neutrophilic dermatosis, POLYSEROSITIS, FAMILIAL PAROXYSMAL, POLYSEROSITIS, RECURRENT, Periodic peritonitis, Benign paroxysmal peritonitis.

## Similar variants {#similar}

Related MEFV variant pages (same residue, condition, or type): [MEFV p.Arg329Cys](/variant/mefv-p-arg329cys), [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), [MEFV p.Ala416Thr](/variant/mefv-p-ala416thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 97557). 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.*