# NM_005911.6(MAT2A):c.249T>C (p.Val83=)

https://sugi.bio/variant/mat2a-p-val83

## Summary

**MAT2A p.Val83= (c.249T>C)** is classified **Likely benign** in MAT2A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-29). Ultra-rare (popmax 0.0334%, mid); Associated with Cardiovascular phenotype.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs370638648 · 2 submitters · 2 linked conditions · ultra-rare (popmax 0.0334%, mid)

## For patients & families {#patients}

This is a change in the MAT2A gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to Cardiovascular phenotype.

*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 | [MAT2A](https://sugi.bio/atlas/gene/MAT2A/) |
| Protein change (HGVS p.) | p.Val83= |
| Coding change (HGVS c.) | c.249T>C |
| MANE Select transcript | [NM_005911](https://www.ncbi.nlm.nih.gov/nuccore/NM_005911) |
| dbSNP | [rs370638648](https://www.ncbi.nlm.nih.gov/snp/rs370638648/) |
| Variant type | single nucleotide variant |
| Location | chr2:85541334-85541334 (GRCh38) |
| ClinVar | [VCV1149715](https://www.ncbi.nlm.nih.gov/clinvar/variation/1149715/) |

**All HGVS expressions:** `NC_000002.11:g.85768457T>C`, `NC_000002.12:g.85541334T>C`, `NG_029183.1:g.7357T>C`, `NM_005911.5:c.249T>C`, `NM_005911.6:c.249T>C`

## 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 4.211, GERP 1.01, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 14.39**. 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: **below the reporting threshold**. This position is scored for a different substitution (T>A, Δ0.89 donor gain), 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 **0.0334%** (mid) · FAF95 0.00588% · FAF99 0.00244% · 2/5,988 in the highest group · 35/1,613,930 alleles overall — ultra-rare (popmax 0.0334%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0334% | 2,994 |
| European (non-Finnish) | 0.00271% | 36,876 |
| Admixed American | 0.00167% | 60,008 |

*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}

**MAT2A** population constraint: LOEUF 0.158, pLI 1, missense-Z 4.6782. *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 thoracic aortic aneurysm and aortic dissection** — Limited (AD)

## Protein context {#protein}

Residue **83** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 96.08, 93% of residues very-high.

**59 experimental structure(s)** (PDB): [2P02](https://www.rcsb.org/structure/2P02), [4KTT](https://www.rcsb.org/structure/4KTT), [4KTV](https://www.rcsb.org/structure/4KTV), [4NDN](https://www.rcsb.org/structure/4NDN), [5A19](https://www.rcsb.org/structure/5A19), [5A1G](https://www.rcsb.org/structure/5A1G) — incl. mutant structure 6FBN.

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

*Describes the biological roles of MAT2A (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:** MAT2A's established molecular role includes methionine adenosyltransferase activity.


### Pathways affected {#pathways}

MAT2A participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Methylation](https://reactome.org/content/detail/R-HSA-156581) | other |

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

**Molecular function:** methionine adenosyltransferase activity, small molecule binding, identical protein binding.

**Biological process:** S-adenosylmethionine biosynthetic process, protein hexamerization, protein heterooligomerization, cellular response to methionine, positive regulation of TORC1 signaling.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-29.

**Submitter consensus:** unanimous (2/2 Likely benign).

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-06-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-29 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [familial thoracic aortic aneurysm and aortic dissection](https://sugi.bio/atlas/disease/familial-thoracic-aortic-aneurysm-and-aortic-dissection/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, Familial thoracic aortic aneurysm and aortic dissection, Thoracic aortic aneurysms and dissections.

## Similar variants {#similar}

Related MAT2A variant pages (same residue, condition, or type): [MAT2A c.292+4T>C](/variant/mat2a-c-292-plus-4t-c), [MAT2A c.549+3A>G](/variant/mat2a-c-549-plus-3a-g), [MAT2A c.952-3T>C](/variant/mat2a-c-952-minus-3t-c), [MAT2A p.Ala11Val](/variant/mat2a-p-ala11val), [MAT2A p.Arg177Cys](/variant/mat2a-p-arg177cys), [MAT2A p.Arg312Gly](/variant/mat2a-p-arg312gly), [MAT2A p.Arg343Gly](/variant/mat2a-p-arg343gly), [MAT2A p.Arg356Cys](/variant/mat2a-p-arg356cys).

### 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 1149715). 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.*