Is MTR p.Arg1164= (c.3492C>A) pathogenic?

MTR p.Arg1164= (c.3492C>A) is classified Benign in MTR (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Common (popmax 45.5%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Disorders of Intracellular Cobalamin Metabolism.

What condition is associated with MTR p.Arg1164= (c.3492C>A)?

MTR p.Arg1164= (c.3492C>A) is associated with Disorders of Intracellular Cobalamin Metabolism, methylcobalamin deficiency type cblG (ClinVar).

MTR p.Arg1164=

Q: How common is MTR p.Arg1164= (c.3492C>A) in the general population?

MTR p.Arg1164= (c.3492C>A) is common (popmax 45.5%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3492C>A · rs12070777 · VCV138283

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 45.5%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

Disorders of Intracellular Cobalamin Metabolism

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 -1.2	GERP -3.4
Overall
CADD	2.063	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 45.5% East Asian · 20,225/44,402 alleles

Filtering AF 45% ClinGen BA1/BS1 input FAF95, joint · FAF99 44.8%

Overall 39.4% 630,757/1,600,128 alleles · common exomes 577,704/1,448,054 · genomes 53,053/152,074 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	57.1%	2
East Asiangrpmax	45.5%	2
Finnishnot grpmax-eligible	44.2%	2
Admixed American	43.5%	2
European (non-Finnish)	40.9%	2
Remaining individualsnot grpmax-eligible	37.5%	3
Ashkenazi Jewishnot grpmax-eligible	32.6%	3
South Asian	31.4%	3
Middle Eastern	30%	3
African / African-American	19.9%	5

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg1164=
Coding: c.3492C>A
MANE Select: NM_000254
dbSNP: rs12070777
Type: single nucleotide variant
Location: chr1:236895444 (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 1164: an α-helix; the adomet activation domain

Full MTR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Disorders of Intracellular Cobalamin Metabolism — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: methylcobalamin deficiency type cblG

Similar variants

MTR p.Arg1164Cys Uncertain significance ★★ ⚠ same residue
MTR p.Arg1164His Benign ★★ 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-arg1164 (accessed [today's date]).

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