Is MAT2A p.Ala40Ser (c.118G>T) pathogenic?

MAT2A p.Ala40Ser (c.118G>T) is classified Uncertain significance in MAT2A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-26). AlphaMissense: likely benign (0.1036); Very rare (popmax 0.000593%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with MAT2A p.Ala40Ser (c.118G>T)?

MAT2A p.Ala40Ser (c.118G>T) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is MAT2A p.Ala40Ser (c.118G>T) in the general population?

MAT2A p.Ala40Ser (c.118G>T) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about MAT2A p.Ala40Ser (c.118G>T)?

AlphaMissense predicts likely benign (score 0.1036) — an in-silico prediction, not a clinical call.

MAT2A p.Ala40Ser

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.118G>T · VCV3707004

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1036 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.1036	likely benign
REVEL	0.707	pathogenic-leaning
SaProt	LLR -9.23	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.28	constrained · MANE · 1,808 bp · p 3e-06 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,179,680 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,624 alleles · very rare exomes 7/1,461,302 · genomes 0/152,322 · joint denominator

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.Ala40Ser
Coding: c.118G>T
MANE Select: NM_005911
Type: single nucleotide variant
Location: chr2:85541109 (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

familial thoracic aortic aneurysm and aortic dissection — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

MAT2A p.Ala40= Benign/Likely benign ★★ 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-ala40ser (accessed [today's date]).

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