Is MTRFR p.Ile111= (c.333C>A) pathogenic?

MTRFR p.Ile111= (c.333C>A) is classified Conflicting classifications of pathogenicity in MTRFR (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-02-13). Ultra-rare (popmax 0.0164%, mid); Associated with combined oxidative phosphorylation defect type 7.

How common is MTRFR p.Ile111= (c.333C>A) in the general population?

MTRFR p.Ile111= (c.333C>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

MTRFR p.Ile111=

Q: What condition is associated with MTRFR p.Ile111= (c.333C>A)?

MTRFR p.Ile111= (c.333C>A) is associated with combined oxidative phosphorylation defect type 7, hereditary spastic paraplegia (ClinVar).

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.333C>A · rs769551356 · VCV1344257

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	GERP -0.33, phastCons 1
Overall
CADD	10.05	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00155% 25/1,613,738 alleles · ultra-rare exomes 23/1,461,676 · genomes 2/152,062 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
South Asian	0.00659%	15,177
Remaining individualsnot grpmax-eligible	0.0032%	31,233
African / African-American	0.00134%	74,862
European (non-Finnish)	0.00127%	78,660

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.Ile111=
Coding: c.333C>A
MANE Select: NM_152269
dbSNP: rs769551356
Type: single nucleotide variant
Location: chr12:123256863 (GRCh38)
Gene constraint: LOEUF 1.224 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.56 · 1 PDB
Residue 111: 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; an α-helix

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

Also linked: hereditary spastic paraplegia

For 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-ile111 (accessed [today's date]).

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