Is MTR p.Pro301Ser (c.901C>T) pathogenic?

MTR p.Pro301Ser (c.901C>T) is classified Uncertain significance in MTR (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-20). AlphaMissense: likely benign (0.185); Very rare (popmax 0.00667%, amr); Associated with methylcobalamin deficiency type cblG.

What condition is associated with MTR p.Pro301Ser (c.901C>T)?

MTR p.Pro301Ser (c.901C>T) is associated with methylcobalamin deficiency type cblG (ClinVar).

How common is MTR p.Pro301Ser (c.901C>T) in the general population?

MTR p.Pro301Ser (c.901C>T) is very rare (popmax 0.00667%, amr) (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.Pro301Ser (c.901C>T)?

AlphaMissense predicts likely benign (score 0.185) — an in-silico prediction, not a clinical call.

MTR p.Pro301Ser

c.901C>T · rs766371534 · VCV1446428

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.185 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

methylcobalamin deficiency type cblG

Computational evidence

Protein change
AlphaMissense	0.185	likely benign
REVEL	0.38	indeterminate
SaProt	LLR -4.50	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.8, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 102 kb · p 9.3e-14 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/59,994 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000248% 4/1,613,634 alleles · very rare

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.Pro301Ser
Coding: c.901C>T
MANE Select: NM_000254
dbSNP: rs766371534
Type: single nucleotide variant
Location: chr1:236825373 (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 301: the hcy-binding domain

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

For Homocystinuria without methylmalonic aciduria (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

Similar variants

MTR p.Pro301Ala Uncertain significance ★★ ⚠ same residue
MTR p.Pro301fs 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

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-pro301ser (accessed [today's date]).

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