Is MTRFR p.Ser89fs (c.264dup) pathogenic?

MTRFR p.Ser89fs (c.264dup) is classified Likely pathogenic in MTRFR (ClinVar, Single submitter, 1 submitter; last evaluated 2026-06-01). Associated with combined oxidative phosphorylation defect type 7.

What condition is associated with MTRFR p.Ser89fs (c.264dup)?

MTRFR p.Ser89fs (c.264dup) is associated with combined oxidative phosphorylation defect type 7 (ClinVar).

MTRFR p.Ser89fs

Q: How is Combined oxidative phosphorylation defect type 7 inherited?

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

c.264dup · VCV4974959

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

combined oxidative phosphorylation defect type 7

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (2 of 3, 22 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6	GERP 1.6, phastCons 0.98

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: MTRFR
Protein: p.Ser89fs
Coding: c.264dup
MANE Select: NM_152269
Type: Duplication
Location: chr12:123253934 (GRCh38)
Gene constraint: LOEUF 1.224 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.56 · 1 PDB
Residue 89: 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); the 'ggq domain' region; a β-strand

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

Disease context

combined oxidative phosphorylation defect type 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Combined oxidative phosphorylation defect type 7 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

MTRFR p.Ser89= Likely benign ★ same residue
MTRFR p.Pro34fs Pathogenic ★★ same condition
MTRFR c.283-19_283-16dup Likely benign ★★ same condition
MTRFR p.Asp48fs Pathogenic ★ same condition
MTRFR p.Pro12fs Pathogenic ★ same condition
MTRFR p.Lys156fs Uncertain significance ★ same condition
MTRFR p.Arg132Ter Pathogenic ★★ same condition
MTRFR p.Arg15Ter 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/mtrfr-p-ser89fs (accessed [today's date]).

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