Is MTR p.Ala818= (c.2454T>C) pathogenic?

MTR p.Ala818= (c.2454T>C) is classified Conflicting classifications of pathogenicity in MTR (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-01-31). Ultra-rare (popmax 0.0164%, mid); Associated with Disorders of Intracellular Cobalamin Metabolism.

What condition is associated with MTR p.Ala818= (c.2454T>C)?

MTR p.Ala818= (c.2454T>C) is associated with Disorders of Intracellular Cobalamin Metabolism, methylcobalamin deficiency type cblG (ClinVar).

How common is MTR p.Ala818= (c.2454T>C) in the general population?

MTR p.Ala818= (c.2454T>C) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

MTR p.Ala818=

c.2454T>C · rs769066955 · VCV296570

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

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 -1.8	GERP -2.4
Overall
CADD	5.445	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000867% 14/1,614,068 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)	0.000932%	107,272

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.Ala818=
Coding: c.2454T>C
MANE Select: NM_000254
dbSNP: rs769066955
Type: single nucleotide variant
Location: chr1:236873821 (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 818: the b12-binding 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-ala818 (accessed [today's date]).

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