Is MTR p.Pro286= (c.858C>T) pathogenic?

MTR p.Pro286= (c.858C>T) is classified Benign/Likely benign in MTR (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-02). Rare (popmax 0.589%, nfe); Associated with Disorders of Intracellular Cobalamin Metabolism.

What condition is associated with MTR p.Pro286= (c.858C>T)?

MTR p.Pro286= (c.858C>T) is associated with Disorders of Intracellular Cobalamin Metabolism, methylcobalamin deficiency type cblG (ClinVar).

How common is MTR p.Pro286= (c.858C>T) in the general population?

MTR p.Pro286= (c.858C>T) is rare (popmax 0.589%, nfe) (gnomAD).

MTR p.Pro286=

c.858C>T · rs146019467 · VCV199000

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.589%, nfe)

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	<0.2	all four deltas below 0.2 · C>G here scores Δ0.31 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.59	GERP -5.1, phastCons 0.009
Overall
CADD	7.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.589% European (non-Finnish) · 6,942/1,178,478 alleles

Filtering AF 0.577% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.573%

Overall 0.568% 9,159/1,612,330 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	2.46%	41
European (non-Finnish)grpmax	0.589%	170
Remaining individualsnot grpmax-eligible	0.455%	220
Admixed American	0.232%	432
South Asian	0.125%	799
African / African-American	0.103%	973
Ashkenazi Jewishnot grpmax-eligible	0.0878%	1,139
Middle Eastern	0.0165%	6,056
East Asian	0.00223%	44,868

Finnish 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.Pro286=
Coding: c.858C>T
MANE Select: NM_000254
dbSNP: rs146019467
Type: single nucleotide variant
Location: chr1:236824212 (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 286: the hcy-binding domain; a β-strand

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-pro286 (accessed [today's date]).

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