Is MTRFR p.Phe119= (c.357C>T) pathogenic?

MTRFR p.Phe119= (c.357C>T) is classified Likely benign in MTRFR (ClinVar, Single submitter, 2 submitters; last evaluated 2023-08-29). Ultra-rare (popmax 0.016%, afr); Associated with Spastic paraplegia.

What condition is associated with MTRFR p.Phe119= (c.357C>T)?

MTRFR p.Phe119= (c.357C>T) is associated with Spastic paraplegia, combined oxidative phosphorylation defect type 7 (ClinVar).

How common is MTRFR p.Phe119= (c.357C>T) in the general population?

MTRFR p.Phe119= (c.357C>T) is ultra-rare (popmax 0.016%, afr) (gnomAD).

MTRFR p.Phe119=

c.357C>T · rs144049612 · VCV2070751

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Conditions

Spastic paraplegia

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 4	GERP 0.76, phastCons 1
Overall
CADD	12.41	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.016% African / African-American · 12/74,794 alleles

Filtering AF 0.00923% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00723%

Overall 0.00112% 18/1,613,596 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,233
Remaining individualsnot grpmax-eligible	0.0048%	20,823
South Asian	0.00329%	30,359

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.Phe119=
Coding: c.357C>T
MANE Select: NM_152269
dbSNP: rs144049612
Type: single nucleotide variant
Location: chr12:123256887 (GRCh38)
Gene constraint: LOEUF 1.224 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.56 · 1 PDB
Residue 119: a UniProt-annotated variant site (in coxpd7; decreased cytochrome c oxidase activity in fibroblasts; severe assembly defects in mitochondrial complexes i, iv and v with a milder defect in the assembly of complex iii; no effect on mitochondrial transcripts, rrnas and trnas levels); a UniProt-annotated variant site (in spg55 and coxpd7; decreased activity of mitochondrial respiratory chain; no effect on mitochondrial morphology); the 'ggq domain' region; an α-helix

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.Phe119Leu Uncertain significance ★ ⚠ 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-phe119 (accessed [today's date]).

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