Is MTR p.Arg648His (c.1943G>A) pathogenic?

MTR p.Arg648His (c.1943G>A) is classified Uncertain significance in MTR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-11). AlphaMissense: likely benign (0.0606); Ultra-rare (popmax 0.0133%, amr); Associated with Inborn genetic diseases.

What condition is associated with MTR p.Arg648His (c.1943G>A)?

MTR p.Arg648His (c.1943G>A) is associated with Inborn genetic diseases, methylcobalamin deficiency type cblG (ClinVar).

How common is MTR p.Arg648His (c.1943G>A) in the general population?

MTR p.Arg648His (c.1943G>A) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about MTR p.Arg648His (c.1943G>A)?

AlphaMissense predicts likely benign (score 0.0606) — an in-silico prediction, not a clinical call.

MTR p.Arg648His

c.1943G>A · rs751565093 · VCV1380450

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0606 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0606	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -5.91	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 0.61	GERP -2.3
Regional constraint	o/e 0.81	unconstrained · MANE · 102 kb · p 9.3e-14 · regional, not allelic
Overall
CADD	15.57	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 0.0133% Admixed American · 8/59,986 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.00558% 90/1,613,838 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,498
European (non-Finnish)	0.00636%	15,732
South Asian	0.00549%	18,216
Remaining individualsnot grpmax-eligible	0.0032%	31,238

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.Arg648His
Coding: c.1943G>A
MANE Select: NM_000254
dbSNP: rs751565093
Type: single nucleotide variant
Location: chr1:236853078 (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 648: an α-helix

Full MTR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: methylcobalamin deficiency type cblG

Similar variants

MTR p.Arg648fs Pathogenic ★★ same residue
MTR p.Arg648Cys Uncertain significance ★ ⚠ 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-arg648his (accessed [today's date]).

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