Is MTRR p.Pro66= (c.198C>T) pathogenic?

MTRR p.Pro66= (c.198C>T) is classified Likely benign in MTRR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-20). Ultra-rare (popmax 0.028%, afr); Associated with methylcobalamin deficiency type cblE.

What condition is associated with MTRR p.Pro66= (c.198C>T)?

MTRR p.Pro66= (c.198C>T) is associated with methylcobalamin deficiency type cblE (ClinVar).

How common is MTRR p.Pro66= (c.198C>T) in the general population?

MTRR p.Pro66= (c.198C>T) is ultra-rare (popmax 0.028%, afr) (gnomAD).

How is Homocystinuria without methylmalonic aciduria inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

MTRR p.Pro66=

c.198C>T · rs776410065 · VCV752707

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.028%, afr)

Conditions

methylcobalamin deficiency type cblE

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -20	GERP -3.2
Overall
CADD	1.717	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.028% African / African-American · 21/74,906 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.00254% 41/1,614,008 alleles · ultra-rare exomes 26/1,461,886 · genomes 15/152,122 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.028%	3,567
Middle Eastern	0.0164%	6,084
South Asian	0.0143%	7,006
East Asian	0.00223%	44,882
Admixed American	0.00167%	60,002
European (non-Finnish)	0.000339%	295,007

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: MTRR
Protein: p.Pro66=
Coding: c.198C>T
MANE Select: NM_002454
dbSNP: rs776410065
Type: single nucleotide variant
Location: chr5:7873441 (GRCh38)
Gene constraint: LOEUF 0.932 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.79 · 2 PDB
Residue 66: the flavodoxin-like domain

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

Disease context

methylcobalamin deficiency type cblE — 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

MTRR c.1057+1G>A Likely pathogenic ★★ same condition
MTRR c.1146+1G>A Likely pathogenic ★★ same condition
MTRR c.1371-1G>A Likely pathogenic ★★ same condition
MTRR c.1676+2T>C Likely pathogenic ★★ same condition
MTRR c.1677-1G>A Pathogenic/Likely pathogenic ★★ same condition
MTRR c.1769+1G>A Pathogenic/Likely pathogenic ★★ same condition
MTRR c.401+1G>A Likely pathogenic ★★ same condition
MTRR c.402-1G>T 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/mtrr-p-pro66 (accessed [today's date]).

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