Is MTR p.Val401fs (c.1200dup) pathogenic?

MTR p.Val401fs (c.1200dup) is classified Pathogenic/Likely pathogenic in MTR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-19). Very rare (popmax 0.00168%, amr); Associated with methylcobalamin deficiency type cblG.

What condition is associated with MTR p.Val401fs (c.1200dup)?

MTR p.Val401fs (c.1200dup) is associated with methylcobalamin deficiency type cblG (ClinVar).

How common is MTR p.Val401fs (c.1200dup) in the general population?

MTR p.Val401fs (c.1200dup) is very rare (popmax 0.00168%, 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.Val401fs

c.1200dup · rs1343645070 · VCV1905103

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00168%, 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 14 of 33
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.9	GERP 0.85, phastCons 1
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00168% Admixed American · 1/59,654 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,611,968 alleles · very rare exomes 3/1,461,874 · genomes 1/150,094 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00168%	59,654
Remaining individualsnot grpmax-eligible	0.0016%	62,444
European (non-Finnish)	0.00017%	589,870

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.Val401fs
Coding: c.1200dup
MANE Select: NM_000254
dbSNP: rs1343645070
Type: Duplication
Location: chr1:236835557 (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 401: the pterin-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.Arg648fs Pathogenic ★★ same condition
MTR p.Asn1018fs Likely pathogenic ★★ same condition
MTR p.His307fs Pathogenic ★★ same condition
MTR c.2474-4dup Benign/Likely benign ★★ same condition
MTR c.2474-5_2474-4dup Benign/Likely benign ★★ same condition
MTR c.610-1_613dup Pathogenic ★ same condition
MTR p.Ala493fs Pathogenic ★ same condition
MTR p.Asp825fs 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-val401fs (accessed [today's date]).

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