Is MTR p.Pro148= (c.444G>A) pathogenic?

MTR p.Pro148= (c.444G>A) is classified Likely benign in MTR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-29). Very rare (popmax 0.00669%, eas); Associated with Inborn genetic diseases.

What condition is associated with MTR p.Pro148= (c.444G>A)?

MTR p.Pro148= (c.444G>A) is associated with Inborn genetic diseases, methylcobalamin deficiency type cblG (ClinVar).

How common is MTR p.Pro148= (c.444G>A) in the general population?

MTR p.Pro148= (c.444G>A) is very rare (popmax 0.00669%, eas) (gnomAD).

MTR p.Pro148=

c.444G>A · rs778868012 · VCV1668878

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.17	GERP -5.4, phastCons 0.008
Overall
CADD	10.03	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00669% East Asian · 3/44,854 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00322% 52/1,613,798 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,951
European (non-Finnish)	0.00381%	26,218
Admixed American	0.00333%	30,009
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,072

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.Pro148=
Coding: c.444G>A
MANE Select: NM_000254
dbSNP: rs778868012
Type: single nucleotide variant
Location: chr1:236810537 (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 148: the hcy-binding domain

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.Pro148Leu 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
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-pro148 (accessed [today's date]).

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