Is MTRFR p.Pro34fs (c.96_99dup) pathogenic?

MTRFR p.Pro34fs (c.9699dup) is classified Pathogenic in MTRFR (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-08-14). Ultra-rare (popmax 0.0119%, nfe); Associated with C12ORF65-related disorders.

What condition is associated with MTRFR p.Pro34fs (c.96_99dup)?

MTRFR p.Pro34fs (c.96_99dup) is associated with C12ORF65-related disorders, combined oxidative phosphorylation defect type 7, hereditary spastic paraplegia 55 (ClinVar).

How common is MTRFR p.Pro34fs (c.96_99dup) in the general population?

MTRFR p.Pro34fs (c.96_99dup) is ultra-rare (popmax 0.0119%, nfe) (gnomAD).

MTRFR p.Pro34fs

c.96_99dup · rs863223926 · VCV214192

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0119%, nfe)

Conditions

C12ORF65-related disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 3
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.56	GERP -0.44
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0119% European (non-Finnish) · 141/1,180,046 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00972%

Overall 0.00967% 156/1,614,064 alleles · ultra-rare exomes 146/1,461,888 · genomes 10/152,176 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.024%	4,166
European (non-Finnish)grpmax	0.0119%	8,369

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro34fs
Coding: c.96_99dup
MANE Select: NM_152269
dbSNP: rs863223926
Type: Duplication
Location: chr12:123253769 (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

C12ORF65-related disorders

Also linked: combined oxidative phosphorylation defect type 7 hereditary spastic paraplegia 55

Similar variants

MTRFR c.283-19_283-16dup Likely benign ★★ same condition
MTRFR p.Asp48fs Pathogenic ★ same condition
MTRFR p.Pro12fs Pathogenic ★ same condition
MTRFR p.Ser89fs Likely pathogenic ★ same condition
MTRFR p.Lys156fs Uncertain significance ★ same condition
MTRFR p.Arg132Ter Pathogenic ★★ same condition
MTRFR p.Arg15Ter Pathogenic/Likely pathogenic ★★ same condition
MTRFR p.Gly72fs 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-pro34fs (accessed [today's date]).

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