Is MAT2A p.Ile252Phe (c.754A>T) pathogenic?

MAT2A p.Ile252Phe (c.754A>T) is classified Uncertain significance in MAT2A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-23). AlphaMissense: ambiguous (0.4757); Very rare (popmax 6.2e-05%); Associated with Cardiovascular phenotype.

What condition is associated with MAT2A p.Ile252Phe (c.754A>T)?

MAT2A p.Ile252Phe (c.754A>T) is associated with Cardiovascular phenotype (ClinVar).

How common is MAT2A p.Ile252Phe (c.754A>T) in the general population?

MAT2A p.Ile252Phe (c.754A>T) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about MAT2A p.Ile252Phe (c.754A>T)?

AlphaMissense predicts ambiguous (score 0.4757) — an in-silico prediction, not a clinical call.

MAT2A p.Ile252Phe

c.754A>T · rs2529632113 · VCV2625407

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4757 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4757	ambiguous
REVEL	0.85	moderately pathogenic-leaning
SaProt	LLR -14.26	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 2.2, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 1,072 bp · p 2.4e-16 · regional, not allelic
Overall
CADD	27.0	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 6.2e-05%

Overall 6.2e-05% 1/1,614,024 alleles · very rare exomes 1/1,461,732 · genomes 0/152,292 · 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.Ile252Phe
Coding: c.754A>T
MANE Select: NM_005911
dbSNP: rs2529632113
Type: single nucleotide variant
Location: chr2:85542359 (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

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

Similar variants

MAT2A c.549+3A>G Uncertain significance ★★ same condition
MAT2A p.Ala11Val Uncertain significance ★★ ⚠ same condition
MAT2A p.Asn6His Uncertain significance ★★ ⚠ same condition
MAT2A p.Asn6Ile Uncertain significance ★★ ⚠ same condition
MAT2A p.Gln4Arg Uncertain significance ★★ ⚠ same condition
MAT2A p.Ile154Val Uncertain significance ★★ ⚠ same condition
MAT2A p.Ile241Val Uncertain significance ★★ ⚠ same condition
MAT2A p.Leu19Phe 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-ile252phe (accessed [today's date]).

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