Is MTR p.Arg991Ter (c.2971C>T) pathogenic?

MTR p.Arg991Ter (c.2971C>T) is classified Pathogenic in MTR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-09). Very rare (popmax 0.00329%, sas); Associated with methylcobalamin deficiency type cblG.

What condition is associated with MTR p.Arg991Ter (c.2971C>T)?

MTR p.Arg991Ter (c.2971C>T) is associated with methylcobalamin deficiency type cblG (ClinVar).

How common is MTR p.Arg991Ter (c.2971C>T) in the general population?

MTR p.Arg991Ter (c.2971C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

How is Homocystinuria without methylmalonic aciduria inherited?

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

MTR p.Arg991Ter

c.2971C>T · rs536238004 · VCV632103

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Conditions

methylcobalamin deficiency type cblG

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 28 of 33
Splicing
SpliceAI	Δ0.20	donor loss, 32 bp away · masked 0 · deltas
Pangolin	Δ0.42	loss · gain 0.36 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.3	GERP 1.9, phastCons 1
Overall
CADD	42.0	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 0.00329% South Asian · 3/91,080 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000929% 15/1,614,202 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,360
East Asian	0.00223%	44,876
Finnishnot grpmax-eligible	0.00156%	64,040
European (non-Finnish)	0.000847%	118,004

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.Arg991Ter
Coding: c.2971C>T
MANE Select: NM_000254
dbSNP: rs536238004
Type: single nucleotide variant
Location: chr1:236889300 (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 991: the adomet activation 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 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
MTR c.609+1088G>A Pathogenic ★★ same condition
MTR c.866-2A>C Pathogenic/Likely pathogenic ★★ same condition
MTR p.Arg1147Ter Pathogenic ★★ same condition
MTR p.Arg585Ter 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-arg991ter (accessed [today's date]).

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