Is MAT1A p.Pro255Ser (c.763C>T) pathogenic?

MAT1A p.Pro255Ser (c.763C>T) is classified Pathogenic/Likely pathogenic in MAT1A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-23). AlphaMissense: likely pathogenic (0.9876); Very rare (popmax 0.000847%, nfe); Associated with methionine adenosyltransferase deficiency.

What condition is associated with MAT1A p.Pro255Ser (c.763C>T)?

MAT1A p.Pro255Ser (c.763C>T) is associated with methionine adenosyltransferase deficiency (ClinVar).

How common is MAT1A p.Pro255Ser (c.763C>T) in the general population?

MAT1A p.Pro255Ser (c.763C>T) is very rare (popmax 0.000847%, nfe) (gnomAD).

What do computational predictors say about MAT1A p.Pro255Ser (c.763C>T)?

AlphaMissense predicts likely pathogenic (score 0.9876) — an in-silico prediction, not a clinical call.

MAT1A p.Pro255Ser

Q: How is Methionine adenosyltransferase I/III deficiency inherited?

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

c.763C>T · rs913435613 · VCV378112

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9876 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

methionine adenosyltransferase deficiency

Computational evidence

Protein change
AlphaMissense	0.9876	likely pathogenic ✓ concordant with ClinVar
REVEL	0.96	strongly pathogenic-leaning
SaProt	LLR -12.51	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.96 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 16 kb · p 6.1e-09 · regional, not allelic
Overall
CADD	29.3	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 0.000847% European (non-Finnish) · 10/1,180,030 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.00062% 10/1,614,082 alleles · very rare exomes 10/1,461,746 · genomes 0/152,336 · 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: MAT1A
Protein: p.Pro255Ser
Coding: c.763C>T
MANE Select: NM_000429
dbSNP: rs913435613
Type: single nucleotide variant
Location: chr10:80276381 (GRCh38)
Gene constraint: LOEUF 0.653 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 96.77 · 4 PDB
Residue 255: an α-helix

Full MAT1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

methionine adenosyltransferase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Methionine adenosyltransferase I/III deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

MAT1A p.Ala259Val Pathogenic ★★ same condition
MAT1A p.Arg199Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
MAT1A p.Arg199His Pathogenic ★★ ⚠ same condition
MAT1A p.Arg264Cys Pathogenic ★★ same condition
MAT1A p.Arg264His Pathogenic ★★ same condition
MAT1A p.Arg292Cys Pathogenic/Likely pathogenic ★★ same condition
MAT1A p.Arg299Cys Pathogenic/Likely pathogenic ★★ same condition
MAT1A p.Asp258Tyr Pathogenic/Likely pathogenic ★★ 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/mat1a-p-pro255ser (accessed [today's date]).

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