Is MTRFR p.Pro18Leu (c.53C>T) pathogenic?

MTRFR p.Pro18Leu (c.53C>T) is classified Uncertain significance in MTRFR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-06). AlphaMissense: likely benign (0.0792); Ultra-rare (popmax 0.0164%, mid); Associated with Spastic paraplegia.

What condition is associated with MTRFR p.Pro18Leu (c.53C>T)?

MTRFR p.Pro18Leu (c.53C>T) is associated with Spastic paraplegia, combined oxidative phosphorylation defect type 7 (ClinVar).

How common is MTRFR p.Pro18Leu (c.53C>T) in the general population?

MTRFR p.Pro18Leu (c.53C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about MTRFR p.Pro18Leu (c.53C>T)?

AlphaMissense predicts likely benign (score 0.0792) — an in-silico prediction, not a clinical call.

MTRFR p.Pro18Leu

c.53C>T · rs930288422 · VCV502352

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0792 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Spastic paraplegia

Computational evidence

Protein change
AlphaMissense	0.0792	likely benign
REVEL	0.126	moderately benign-leaning
SaProt	LLR -6.27	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 -5.1	GERP -3.1
Regional constraint	o/e 0.99	unconstrained · MANE · 3,353 bp · p 0.89 · regional, not allelic
Overall
CADD	1.711	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000372% 6/1,614,016 alleles · ultra-rare exomes 4/1,461,890 · genomes 2/152,126 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
African / African-American	0.00267%	37,447
East Asian	0.00223%	44,886
European (non-Finnish)	8.47e-05%	1,180,040

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: MTRFR
Protein: p.Pro18Leu
Coding: c.53C>T
MANE Select: NM_152269
dbSNP: rs930288422
Type: single nucleotide variant
Location: chr12:123253727 (GRCh38)
Gene constraint: LOEUF 1.224 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.56 · 1 PDB

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

Disease context

Spastic paraplegia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: combined oxidative phosphorylation defect type 7

Similar variants

MTRFR p.Pro18= Conflicting classifications of pathogenicity ★ same residue
MTRFR p.Arg132Ter Pathogenic ★★ same condition
MTRFR p.Arg15Ter Pathogenic/Likely pathogenic ★★ same condition
MTRFR c.*439C>T Uncertain significance ★★ same condition
MTRFR p.Ala145Thr Uncertain significance ★★ ⚠ same condition
MTRFR p.Ala19Val Uncertain significance ★★ ⚠ same condition
MTRFR p.Arg109Trp Uncertain significance ★★ ⚠ same condition
MTRFR p.Arg24Gln Uncertain significance ★★ ⚠ 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/mtrfr-p-pro18leu (accessed [today's date]).

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