Is MTR p.Val345Ile (c.1033G>A) pathogenic?

MTR p.Val345Ile (c.1033G>A) is classified Benign/Likely benign in MTR (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0727); Low-frequency (popmax 1.64%, afr); Associated with Disorders of Intracellular Cobalamin Metabolism.

How common is MTR p.Val345Ile (c.1033G>A) in the general population?

MTR p.Val345Ile (c.1033G>A) is low-frequency (popmax 1.64%, afr) (gnomAD).

What do computational predictors say about MTR p.Val345Ile (c.1033G>A)?

AlphaMissense predicts likely benign (score 0.0727) — an in-silico prediction, not a clinical call.

MTR p.Val345Ile

Q: What condition is associated with MTR p.Val345Ile (c.1033G>A)?

MTR p.Val345Ile (c.1033G>A) is associated with Disorders of Intracellular Cobalamin Metabolism, methylcobalamin deficiency type cblG (ClinVar).

c.1033G>A · rs145006491 · VCV296557

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0727 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.64%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Disorders of Intracellular Cobalamin Metabolism

Computational evidence

Protein change
AlphaMissense	0.0727	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -1.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 102 kb · p 9.3e-14 · regional, not allelic
Overall
CADD	16.46	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 1.64% African / African-American · 1,229/74,996 alleles

Filtering AF 1.56% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.53%

Overall 0.0848% 1,368/1,614,010 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.64%	61
Remaining individualsnot grpmax-eligible	0.102%	977
Admixed American	0.0833%	1,201
Middle Eastern	0.033%	3,031
European (non-Finnish)	0.00186%	53,634
South Asian	0.0011%	91,078

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.Val345Ile
Coding: c.1033G>A
MANE Select: NM_000254
dbSNP: rs145006491
Type: single nucleotide variant
Location: chr1:236829226 (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

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-val345ile (accessed [today's date]).

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