Is MTR p.Pro749Ser (c.2245C>T) pathogenic?

MTR p.Pro749Ser (c.2245C>T) is classified Uncertain significance in MTR (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-06-04). AlphaMissense: ambiguous (0.449); Rare (popmax 0.153%, nfe); Associated with Disorders of Intracellular Cobalamin Metabolism.

What condition is associated with MTR p.Pro749Ser (c.2245C>T)?

MTR p.Pro749Ser (c.2245C>T) is associated with Disorders of Intracellular Cobalamin Metabolism, intellectual disability, methylcobalamin deficiency type cblG (ClinVar).

How common is MTR p.Pro749Ser (c.2245C>T) in the general population?

MTR p.Pro749Ser (c.2245C>T) is rare (popmax 0.153%, nfe) (gnomAD).

What do computational predictors say about MTR p.Pro749Ser (c.2245C>T)?

AlphaMissense predicts ambiguous (score 0.449) — an in-silico prediction, not a clinical call.

MTR p.Pro749Ser

c.2245C>T · rs142250261 · VCV296568

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.449 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.153%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Disorders of Intracellular Cobalamin Metabolism

Computational evidence

Protein change
AlphaMissense	0.449	ambiguous
REVEL	0.748	pathogenic-leaning
SaProt	LLR -13.46	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 102 kb · p 9.3e-14 · regional, not allelic
Overall
CADD	28.5	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 0.153% European (non-Finnish) · 1,807/1,179,896 alleles

Filtering AF 0.147% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.145%

Overall 0.125% 2,013/1,613,836 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.153%	653
Finnishnot grpmax-eligible	0.147%	681
Remaining individualsnot grpmax-eligible	0.112%	892
Admixed American	0.0283%	3,529
African / African-American	0.0267%	3,745
South Asian	0.00439%	22,772
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596

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.Pro749Ser
Coding: c.2245C>T
MANE Select: NM_000254
dbSNP: rs142250261
Type: single nucleotide variant
Location: chr1:236862284 (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 749: the b12-binding n-terminal 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: intellectual disability methylcobalamin deficiency type cblG

Similar variants

MTR p.Pro749= Likely benign ★ 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-pro749ser (accessed [today's date]).

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