Benign
Multiple submitters
Classification
Benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 7 submitters
gnomAD v4.1
Common
common (popmax 24.8%, eas) — too common for a highly-penetrant pathogenic allele
Conditions
1
combined oxidative phosphorylation defect type 7
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | all four deltas below 0.2 · C>A here scores Δ0.20 · evaluated, not missing |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -1.9 | GERP -1.7 |
| Overall | ||
| CADD | 9.77 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
24.8%
East Asian · 11,110/44,854 alleles
Filtering AF
24.4%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 24.2%
Overall
4.4%
71,053/1,614,058 alleles · common
exomes 63,741/1,461,818 · genomes 7,312/152,240 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 24.8% | 4 |
| Amishnot grpmax-eligible | 8.33% | 12 |
| Admixed American | 6.12% | 16 |
| Remaining individualsnot grpmax-eligible | 5.22% | 19 |
| Middle Eastern | 4.62% | 22 |
| South Asian | 4.4% | 23 |
| African / African-American | 4.35% | 23 |
| Ashkenazi Jewishnot grpmax-eligible | 3.71% | 27 |
| European (non-Finnish) | 3.6% | 28 |
| Finnishnot grpmax-eligible | 2.74% | 37 |
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.Ile91=
- Coding
- c.273C>T
- MANE Select
- NM_152269
- dbSNP
- rs2280424
- Type
- single nucleotide variant
- Location
- chr12:123253947 (GRCh38)
- Gene constraint
- LOEUF 1.224 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 83.56 · 1 PDB
- Residue 91
- 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
Disease context
combined oxidative phosphorylation defect type 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsFor Combined oxidative phosphorylation defect type 7 (Orphanet):
- Inheritance
- Autosomal recessive
- Onset
- Childhood, Infancy
Similar variants
- 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
- MTRFR p.Arg24Leu 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-ile91 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown