Is MTR p.Ser450Asp (c.1348_1349inv) pathogenic?

MTR p.Ser450Asp (c.13481349inv) is classified Conflicting classifications of pathogenicity in MTR (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-03-20). Associated with methylcobalamin deficiency type cblG.

What condition is associated with MTR p.Ser450Asp (c.1348_1349inv)?

MTR p.Ser450Asp (c.1348_1349inv) is associated with methylcobalamin deficiency type cblG, neural tube defects, folate-sensitive (ClinVar).

How is Homocystinuria without methylmalonic aciduria inherited?

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

MTR p.Ser450Asp

c.1348_1349inv · VCV1374754

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

Conditions

methylcobalamin deficiency type cblG

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 102 kb · p 9.3e-14 · regional, not allelic

Variant & gene context

Gene: MTR
Protein: p.Ser450Asp
Coding: c.1348_1349inv
MANE Select: NM_000254
Type: Inversion
Location: chr1:236838432 (GRCh38)
Gene constraint: LOEUF 0.625 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.60 · 9 PDB
Residue 450: the pterin-binding domain

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

Disease context

methylcobalamin deficiency type cblG — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neural tube defects, folate-sensitive

For Homocystinuria without methylmalonic aciduria (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

MTR p.Ser450= Likely benign ★ same residue
MTR p.Ala1048Val Uncertain significance ★ same condition
MTR c.2474-17_2474-16inv Likely benign ★ same condition
MTR c.2474-19_2474-18inv Likely benign ★ same condition
MTR c.1812+1G>A Likely pathogenic ★★ same condition
MTR c.2474-1G>C Pathogenic ★★ same condition
MTR c.2595-2A>G Likely pathogenic ★★ same condition
MTR c.340-166A>G 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/mtr-p-ser450asp (accessed [today's date]).

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