Is MTR p.Leu206fs (c.617del) pathogenic?

MTR p.Leu206fs (c.617del) is classified Pathogenic in MTR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-28). Very rare (popmax 0.00666%, amr); Associated with methylcobalamin deficiency type cblG.

What condition is associated with MTR p.Leu206fs (c.617del)?

MTR p.Leu206fs (c.617del) is associated with methylcobalamin deficiency type cblG (ClinVar).

How common is MTR p.Leu206fs (c.617del) in the general population?

MTR p.Leu206fs (c.617del) is very rare (popmax 0.00666%, amr) (gnomAD).

How is Homocystinuria without methylmalonic aciduria inherited?

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

MTR p.Leu206fs

c.617del · rs768968736 · VCV2898714

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00666%, amr)

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 7 of 33
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.14	GERP -0.77, phastCons 0.45

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00666% Admixed American · 4/60,018 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000342% 5/1,461,652 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00666%	15,004
European (non-Finnish)	8.48e-05%	1,179,869

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: MTR
Protein: p.Leu206fs
Coding: c.617del
MANE Select: NM_000254
dbSNP: rs768968736
Type: Deletion
Location: chr1:236815610 (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 206: the hcy-binding domain; an α-helix

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-leu206fs (accessed [today's date]).

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