Is MTR p.Glu684fs (c.2049_2058del) pathogenic?

MTR p.Glu684fs (c.20492058del) is classified Pathogenic in MTR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-12). Associated with methylcobalamin deficiency type cblG.

What condition is associated with MTR p.Glu684fs (c.2049_2058del)?

MTR p.Glu684fs (c.2049_2058del) is associated with methylcobalamin deficiency type cblG (ClinVar).

How is Homocystinuria without methylmalonic aciduria inherited?

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

MTR p.Glu684fs

c.2049_2058del · VCV3645491

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

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.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 20 of 33
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.8	GERP 2.8, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: MTR
Protein: p.Glu684fs
Coding: c.2049_2058del
MANE Select: NM_000254
Type: Deletion
Location: chr1:236861127 (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 684: the b12-binding n-terminal 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

For Homocystinuria without methylmalonic aciduria (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

MTR p.Ala935fs Pathogenic ★★ same condition
MTR p.Ile1201fs Pathogenic ★★ same condition
MTR p.Ile881del Uncertain significance ★★ same condition
MTR c.2474-18_2474-17del Benign/Likely benign ★★ same condition
MTR c.2474-18del Benign ★★ same condition
MTR c.2474-19_2474-15del Likely benign ★★ same condition
MTR c.*16del Benign ★★ same condition
MTR c.2044-1_2047del 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-glu684fs (accessed [today's date]).

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