Is MAT2A p.Ala40= (c.120T>C) pathogenic?

MAT2A p.Ala40= (c.120T>C) is classified Benign/Likely benign in MAT2A (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-03-10). Ultra-rare (popmax 0.0868%, sas); Associated with Cardiovascular phenotype.

What condition is associated with MAT2A p.Ala40= (c.120T>C)?

MAT2A p.Ala40= (c.120T>C) is associated with Cardiovascular phenotype, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is MAT2A p.Ala40= (c.120T>C) in the general population?

MAT2A p.Ala40= (c.120T>C) is ultra-rare (popmax 0.0868%, sas) (gnomAD).

MAT2A p.Ala40=

c.120T>C · rs570063081 · VCV1750084

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0868%, sas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.94	GERP 0.95, phastCons 1
Overall
CADD	12.74	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0868% South Asian · 79/91,016 alleles

Filtering AF 0.0713% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0657%

Overall 0.00824% 133/1,613,734 alleles · ultra-rare exomes 122/1,461,384 · genomes 11/152,350 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0868%	1,152
Remaining individualsnot grpmax-eligible	0.008%	12,498
African / African-American	0.00533%	18,764
European (non-Finnish)	0.00381%	26,216

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MAT2A
Protein: p.Ala40=
Coding: c.120T>C
MANE Select: NM_005911
dbSNP: rs570063081
Type: single nucleotide variant
Location: chr2:85541111 (GRCh38)
Gene constraint: LOEUF 0.158 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 96.08 · 59 PDB
Residue 40: an α-helix

Full MAT2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial thoracic aortic aneurysm and aortic dissection

Similar variants

MAT2A p.Ala40Ser Uncertain significance ★ ⚠ same residue
MAT2A c.292+4T>C Uncertain significance ★★ same condition
MAT2A c.549+3A>G Uncertain significance ★★ same condition
MAT2A c.952-3T>C Uncertain significance ★★ same condition
MAT2A p.Ala11Val Uncertain significance ★★ ⚠ same condition
MAT2A p.Arg177Cys Uncertain significance ★★ ⚠ same condition
MAT2A p.Arg312Gly Uncertain significance ★★ ⚠ same condition
MAT2A p.Arg343Gly Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mat2a-p-ala40 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown