Is MTR p.Arg1027Trp (c.3079C>T) pathogenic?

MTR p.Arg1027Trp (c.3079C>T) is classified Conflicting classifications of pathogenicity in MTR (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1102); Rare (popmax 0.483%, nfe); Associated with Disorders of Intracellular Cobalamin Metabolism.

How common is MTR p.Arg1027Trp (c.3079C>T) in the general population?

MTR p.Arg1027Trp (c.3079C>T) is rare (popmax 0.483%, nfe) (gnomAD).

What do computational predictors say about MTR p.Arg1027Trp (c.3079C>T)?

AlphaMissense predicts likely benign (score 0.1102) — an in-silico prediction, not a clinical call.

MTR p.Arg1027Trp

Q: What condition is associated with MTR p.Arg1027Trp (c.3079C>T)?

MTR p.Arg1027Trp (c.3079C>T) is associated with Disorders of Intracellular Cobalamin Metabolism, methylcobalamin deficiency type cblG (ClinVar).

c.3079C>T · rs116836001 · VCV203839

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1102 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.483%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Disorders of Intracellular Cobalamin Metabolism

Computational evidence

Protein change
AlphaMissense	0.1102	likely benign
REVEL	0.286	benign-leaning
SaProt	LLR -10.98	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 1.5, phastCons 0.83
Regional constraint	o/e 0.81	unconstrained · MANE · 102 kb · p 9.3e-14 · regional, not allelic
Overall
CADD	24.5	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 0.483% European (non-Finnish) · 5,699/1,180,014 alleles

Filtering AF 0.472% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.468%

Overall 0.41% 6,612/1,614,076 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.483%	207
Remaining individualsnot grpmax-eligible	0.363%	275
Finnishnot grpmax-eligible	0.347%	288
South Asian	0.279%	359
Admixed American	0.232%	432
African / African-American	0.0707%	1,415
Middle Eastern	0.0495%	2,021
Ashkenazi Jewishnot grpmax-eligible	0.0203%	4,934
East Asian	0.0201%	4,986

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.Arg1027Trp
Coding: c.3079C>T
MANE Select: NM_000254
dbSNP: rs116836001
Type: single nucleotide variant
Location: chr1:236891204 (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 1027: a β-strand; the adomet activation 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: methylcobalamin deficiency type cblG

Similar variants

MTR p.Arg1027Gln Conflicting classifications of pathogenicity ★ ⚠ 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-arg1027trp (accessed [today's date]).

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