Is MAT2A p.Gln4Pro (c.11A>C) pathogenic?

MAT2A p.Gln4Pro (c.11A>C) is classified Uncertain significance in MAT2A (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-24). AlphaMissense: likely benign (0.0835); Very rare (popmax 0.00034%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with MAT2A p.Gln4Pro (c.11A>C)?

MAT2A p.Gln4Pro (c.11A>C) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is MAT2A p.Gln4Pro (c.11A>C) in the general population?

MAT2A p.Gln4Pro (c.11A>C) is very rare (popmax 0.00034%, nfe) (gnomAD).

What do computational predictors say about MAT2A p.Gln4Pro (c.11A>C)?

AlphaMissense predicts likely benign (score 0.0835) — an in-silico prediction, not a clinical call.

MAT2A p.Gln4Pro

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.11A>C · rs756268499 · VCV840588

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0835 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00034%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.0835	likely benign
REVEL	0.453	indeterminate
SaProt	LLR -8.11	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.57, phastCons 1
Regional constraint	o/e 1.49	unconstrained · MANE · 54 bp · p 0.017 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00034% European (non-Finnish) · 4/1,176,042 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000249% 4/1,604,292 alleles · very rare exomes 4/1,451,978 · genomes 0/152,314 · 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.Gln4Pro
Coding: c.11A>C
MANE Select: NM_005911
dbSNP: rs756268499
Type: single nucleotide variant
Location: chr2:85539298 (GRCh38)
Gene constraint: LOEUF 0.158 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 96.08 · 59 PDB

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.Gln4Arg Uncertain significance ★★ ⚠ same residue
MAT2A p.Gln4= Likely benign ★★ same residue
MAT2A p.Gln4His 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

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-gln4pro (accessed [today's date]).

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