Is MTR p.Arg52Gln (c.155G>A) pathogenic?

MTR p.Arg52Gln (c.155G>A) is classified Benign/Likely benign in MTR (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-05-01). AlphaMissense: likely benign (0.142); Rare (popmax 0.775%, nfe); Associated with Disorders of Intracellular Cobalamin Metabolism.

What condition is associated with MTR p.Arg52Gln (c.155G>A)?

MTR p.Arg52Gln (c.155G>A) is associated with Disorders of Intracellular Cobalamin Metabolism, methylcobalamin deficiency type cblG (ClinVar).

How common is MTR p.Arg52Gln (c.155G>A) in the general population?

MTR p.Arg52Gln (c.155G>A) is rare (popmax 0.775%, nfe) (gnomAD).

What do computational predictors say about MTR p.Arg52Gln (c.155G>A)?

AlphaMissense predicts likely benign (score 0.142) — an in-silico prediction, not a clinical call.

MTR p.Arg52Gln

c.155G>A · rs12749581 · VCV534573

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.142 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.775%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Disorders of Intracellular Cobalamin Metabolism

Computational evidence

Protein change
AlphaMissense	0.142	likely benign
REVEL	0.137	moderately benign-leaning
SaProt	LLR -5.40	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.28	donor gain · deltas
Pangolin	Δ0.34	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.9	GERP -2.8, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 102 kb · p 9.3e-14 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.775% European (non-Finnish) · 9,142/1,180,020 alleles

Filtering AF 0.761% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.756%

Overall 0.622% 10,035/1,614,150 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.775%	129
Finnishnot grpmax-eligible	0.558%	179
Remaining individualsnot grpmax-eligible	0.448%	223
Admixed American	0.252%	397
African / African-American	0.107%	938
Ashkenazi Jewishnot grpmax-eligible	0.027%	3,701
South Asian	0.0176%	5,692
East Asian	0.00223%	44,882

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.Arg52Gln
Coding: c.155G>A
MANE Select: NM_000254
dbSNP: rs12749581
Type: single nucleotide variant
Location: chr1:236803548 (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 52: the hcy-binding domain; a UniProt-annotated variant site (in)

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.Arg52Ter 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
MTR p.Arg1147Ter 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-arg52gln (accessed [today's date]).

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