Is MTR p.Asp1159= (c.3477C>T) pathogenic?

MTR p.Asp1159= (c.3477C>T) is classified Benign in MTR (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-01). Low-frequency (popmax 3.32%, eas); Associated with Disorders of Intracellular Cobalamin Metabolism.

What condition is associated with MTR p.Asp1159= (c.3477C>T)?

MTR p.Asp1159= (c.3477C>T) is associated with Disorders of Intracellular Cobalamin Metabolism, methylcobalamin deficiency type cblG (ClinVar).

How common is MTR p.Asp1159= (c.3477C>T) in the general population?

MTR p.Asp1159= (c.3477C>T) is low-frequency (popmax 3.32%, eas) (gnomAD).

MTR p.Asp1159=

c.3477C>T · rs117061132 · VCV296577

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.32%, eas)

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 -6.6	GERP -2.3
Overall
CADD	3.628	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.32% East Asian · 1,483/44,628 alleles

Filtering AF 3.18% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.13%

Overall 0.107% 1,723/1,604,488 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	3.32%	30
Remaining individualsnot grpmax-eligible	0.184%	545
South Asian	0.0696%	1,437
African / African-American	0.0374%	2,676
Admixed American	0.0186%	5,369
European (non-Finnish)	0.00213%	47,011

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.Asp1159=
Coding: c.3477C>T
MANE Select: NM_000254
dbSNP: rs117061132
Type: single nucleotide variant
Location: chr1:236895429 (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 1159: 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 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-asp1159 (accessed [today's date]).

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