Is MTR p.Arg703= (c.2109A>G) pathogenic?

MTR p.Arg703= (c.2109A>G) is classified Likely benign in MTR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-12). Very rare (popmax 0.0088%, sas); Associated with methylcobalamin deficiency type cblG.

What condition is associated with MTR p.Arg703= (c.2109A>G)?

MTR p.Arg703= (c.2109A>G) is associated with methylcobalamin deficiency type cblG (ClinVar).

How common is MTR p.Arg703= (c.2109A>G) in the general population?

MTR p.Arg703= (c.2109A>G) is very rare (popmax 0.0088%, 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.Arg703=

c.2109A>G · rs565935347 · VCV1106147

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0088%, sas)

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 · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.11	GERP -5.4, phastCons 0.18
Overall
CADD	4.733	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0088% South Asian · 8/90,944 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00313%

Overall 0.000683% 11/1,611,212 alleles · very rare exomes 9/1,461,598 · genomes 2/149,614 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0088%	11,368
East Asian	0.00223%	44,792
Remaining individualsnot grpmax-eligible	0.0016%	62,452
European (non-Finnish)	8.48e-05%	1,179,536

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.Arg703=
Coding: c.2109A>G
MANE Select: NM_000254
dbSNP: rs565935347
Type: single nucleotide variant
Location: chr1:236861190 (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 703: 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.Arg703Gln Uncertain significance ★★ ⚠ same residue
MTR p.Arg703Ter Pathogenic ★ same residue
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

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-arg703 (accessed [today's date]).

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