Is MTR p.Arg514Ser (c.1542A>T) pathogenic?

MTR p.Arg514Ser (c.1542A>T) is classified Conflicting classifications of pathogenicity in MTR (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-02). AlphaMissense: likely benign (0.1629); Rare (popmax 0.114%, eas); Associated with methylcobalamin deficiency type cblG.

What condition is associated with MTR p.Arg514Ser (c.1542A>T)?

MTR p.Arg514Ser (c.1542A>T) is associated with methylcobalamin deficiency type cblG, neural tube defects, folate-sensitive (ClinVar).

How common is MTR p.Arg514Ser (c.1542A>T) in the general population?

MTR p.Arg514Ser (c.1542A>T) is rare (popmax 0.114%, eas) (gnomAD).

How is Homocystinuria without methylmalonic aciduria inherited?

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

What do computational predictors say about MTR p.Arg514Ser (c.1542A>T)?

AlphaMissense predicts likely benign (score 0.1629) — an in-silico prediction, not a clinical call.

MTR p.Arg514Ser

c.1542A>T · rs200479834 · VCV853952

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1629 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.114%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

methylcobalamin deficiency type cblG

Computational evidence

Protein change
AlphaMissense	0.1629	likely benign
REVEL	0.325	indeterminate
SaProt	LLR -11.31	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.053	GERP -5
Regional constraint	o/e 0.81	unconstrained · MANE · 102 kb · p 9.3e-14 · regional, not allelic
Overall
CADD	6.15	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 0.114% East Asian · 51/44,844 alleles

Filtering AF 0.0888% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.08%

Overall 0.00415% 67/1,613,464 alleles · rare exomes 60/1,461,316 · genomes 7/152,148 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.114%	879
Remaining individualsnot grpmax-eligible	0.0192%	5,207
Admixed American	0.00167%	59,968
European (non-Finnish)	0.000254%	393,218

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.Arg514Ser
Coding: c.1542A>T
MANE Select: NM_000254
dbSNP: rs200479834
Type: single nucleotide variant
Location: chr1:236850370 (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 514: the pterin-binding domain; an α-helix

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

Also linked: neural tube defects, folate-sensitive

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-arg514ser (accessed [today's date]).

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