Is MTR p.Val765Ala (c.2294T>C) pathogenic?

MTR p.Val765Ala (c.2294T>C) is classified Uncertain significance in MTR (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-12). AlphaMissense: likely benign (0.0611); Very rare (popmax 0.00167%, amr); Associated with methylcobalamin deficiency type cblG.

What condition is associated with MTR p.Val765Ala (c.2294T>C)?

MTR p.Val765Ala (c.2294T>C) is associated with methylcobalamin deficiency type cblG (ClinVar).

How common is MTR p.Val765Ala (c.2294T>C) in the general population?

MTR p.Val765Ala (c.2294T>C) is very rare (popmax 0.00167%, 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.Val765Ala (c.2294T>C)?

AlphaMissense predicts likely benign (score 0.0611) — an in-silico prediction, not a clinical call.

MTR p.Val765Ala

c.2294T>C · rs931972359 · VCV1355820

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0611 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

methylcobalamin deficiency type cblG

Computational evidence

Protein change
AlphaMissense	0.0611	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -6.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.29	GERP 0.33
Regional constraint	o/e 0.81	unconstrained · MANE · 102 kb · p 9.3e-14 · regional, not allelic
Overall
CADD	0.147	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 0.00167% Admixed American · 1/60,020 alleles

Overall 0.000186% 3/1,613,230 alleles · very rare exomes 3/1,460,942 · genomes 0/152,288 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,020
Remaining individualsnot grpmax-eligible	0.0016%	62,448
European (non-Finnish)	8.48e-05%	1,179,254

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.Val765Ala
Coding: c.2294T>C
MANE Select: NM_000254
dbSNP: rs931972359
Type: single nucleotide variant
Location: chr1:236862333 (GRCh38)
Gene constraint: LOEUF 0.625 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.60 · 9 PDB

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

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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-val765ala (accessed [today's date]).

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