FXN

Chr 9AR

frataxin

Also known as: CyaY, FA, FARR, FRDA, X25

NCBI Gene: 2395ENSG00000165060UniProt: Q16595

This nuclear gene encodes a mitochondrial protein which belongs to the FRATAXIN family. The protein functions in regulating mitochondrial iron transport and respiration. The expansion of intronic trinucleotide repeat GAA from 8-33 repeats to >90 repeats results in Friedreich ataxia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]

Primary Disease Associations & Inheritance

Friedreich ataxiaMIM #229300
AR
Friedreich ataxia with retained reflexesMIM #229300
AR
193
ClinVar variants
67
Pathogenic / LP
0.34
pLI score
10
Active trials
Clinical Summary— FXN
🧬
Gene-Disease Validity (ClinGen)
Friedreich ataxia · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.
📋
ClinVar Variants
67 Pathogenic / Likely Pathogenic· 72 VUS of 193 total submissions
💊
Clinical Trials
10 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.72LOEUF
pLI 0.345
Z-score 2.11
OE 0.23 (0.09–0.72)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.28Z-score
OE missense 0.92 (0.78–1.09)
94 obs / 102.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.23 (0.09–0.72)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.92 (0.78–1.09)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.06
0≤1.21.6
LoF obs/exp: 2 / 8.7Missense obs/exp: 94 / 102.1Syn Z: -0.34

ClinVar Variant Classifications

193 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic49
Likely Pathogenic18
VUS72
Likely Benign20
Benign25
Conflicting9
49
Pathogenic
18
Likely Pathogenic
72
VUS
20
Likely Benign
25
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
4
40
0
49
Likely Pathogenic
6
3
9
0
18
VUS
1
50
18
3
72
Likely Benign
0
7
4
9
20
Benign
0
3
18
4
25
Conflicting
—9
Total12678916193

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

FXN · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

FXN-related Friedreich ataxia

definitive
ARLoss Of FunctionAltered Gene Product Structure, Decreased Gene Product Level
Dev. DisordersCardiac
G2P ↗
splice region variantstart lostinframe deletioninframe insertionsplice donor variant NMD triggeringframeshift variant NMD triggeringsplice acceptor variant NMD triggering

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
FRATAXIN; FXN
MIM #606829 · *

Friedreich ataxia

MIM #229300

Molecular basis of disorder known

Autosomal recessive

Friedreich ataxia with retained reflexes

MIM #229300

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — FXN
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Frataxin deficiency promotes endothelial senescence in pulmonary hypertension.
Culley MK et al.·J Clin Invest
2021
Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study.
Ibañez K et al.·Lancet Neurol
2022
Hereditary Ataxias in Argentina.
Rossi M et al.·Cerebellum
2025Review
Human frataxin, the Friedreich ataxia deficient protein, interacts with mitochondrial respiratory chain.
Doni D et al.·Cell Death Dis
2023
Safety and efficacy of omaveloxolone v/s placebo for the treatment of Friedreich's ataxia in patients aged more than 16 years: a systematic review.
Umrao A et al.·Orphanet J Rare Dis
2024Review
Compound heterozygous FXN mutations and clinical outcome in friedreich ataxia.
Galea CA et al.·Ann Neurol
2016
Base editing of trinucleotide repeats that cause Huntington's disease and Friedreich's ataxia reduces somatic repeat expansions in patient cells and in mice.
Matuszek Z et al.·Nat Genet
2025
Evaluating mFARS in pediatric Friedreich's ataxia: Insights from the FACHILD study.
Rummey C et al.·Ann Clin Transl Neurol
2024
FXN gene methylation determines carrier status in Friedreich ataxia.
Lam C et al.·J Med Genet
2023
Repeat-associated ataxias in a German patient cohort analysed by targeted parallel long-read sequencing.
Erdmann H et al.·Brain
2026Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
NFS1, together with FXN, protects cells from ferroptosis and DNA damage in diffuse large B-cell lymphoma.
Shi X et al.·Redox Biol
2025🔓 Open Access
Inhibition of Rho-Associated Kinases ROCK1 and ROCK2 as a Therapeutic Strategy to Reactivate the Repressed FXN Gene in Friedreich Ataxia.
Fang M et al.·J Neurosci
2025
Targeting RPLP2 Triggers DLBCL Ferroptosis by Decreasing FXN Expression.
Guo J et al.·Biomedicines
2025🔓 Open Access
Metformin aggravates pancreatitis by regulating the release of oxidised mitochondrial DNA via the frataxin (FXN)/ninjurin 1 (NINJ1) signalling pathway.
Xin G et al.·Br J Pharmacol
2025
MSH2 is not required for either maintenance of DNA methylation or repeat contraction at the FMR1 locus in fragile X syndrome or the FXN locus in Friedreich's ataxia.
Grant-Bier J et al.·Epigenetics Chromatin
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Friedreich's Ataxia (FA)

A Study of SGT-212 Gene Therapy in Friedreich's Ataxia

RECRUITING
NCT07180355Phase PHASE1Solid Biosciences Inc.Started 2025-10-22
SGT-212
Friedreich Ataxia

Characterisation of the Cognitive Profile of Patients Suffering From Friedreich's Ataxia

RECRUITING
NCT05874388Institut National de la Santé Et de la Recherche Médicale, FranceStarted 2023-06-19
Spinocerebellar Ataxia 27B (SCA27B)

A Randomized, Parallel-arm, Double Blind, Placebo-controlled Study to Assess the Efficacy of Fampridine for Patients With Spinocerebellar Ataxia SCA27B Caused by a GAA Expansion in the FGF14 Gene

RECRUITING
NCT07185347Phase PHASE3Assistance Publique - Hôpitaux de ParisStarted 2025-10-21
Fampridine 10 mg prolonged-release tablet (per os)Placebo (tablets per os)
Rare DisordersUndiagnosed DisordersDisorders of Unknown Prevalence

Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

RECRUITING
NCT01793168Sanford HealthStarted 2010-07
Friedreich Ataxia

A Natural History Study to TRACK Brain and Spinal Cord Changes in Individuals with Friedreich Ataxia (TRACK-FA)

ACTIVE NOT RECRUITING
NCT04349514Monash UniversityStarted 2021-02-10
Natural history
Friedreich's Ataxia

Biomarkers in Friedreich's Ataxia

RECRUITING
NCT02497534University of FloridaStarted 2015-09
Friedreich Ataxia

An Open Label Extension Study of CTI-1601 in Subjects With Friedreich's Ataxia

ENROLLING BY INVITATION
NCT06447025Phase PHASE2Larimar Therapeutics, Inc.Started 2024-01-25
CTI-1601
Friedreich AtaxiaCardiomyopathiesCardiac Hypertrophy

Phase IA and IB Study of AAVrh.10hFXN Gene Therapy for the Cardiomyopathy of Friedreich's Ataxia

RECRUITING
NCT05302271Phase PHASE1Weill Medical College of Cornell UniversityStarted 2022-02-22
AAVrh.10hFXN, serotype rh.10 adeno-associated virus (AAV) gene transfer vector expressing the cDNA coding for human FXNPrednisone
Friedreich&#39;s AtaxiaSteroidogenesis

FRIEDREICH ATAXIA- STEROIDOGENESIS

RECRUITING
NCT07123142Istanbul UniversityStarted 2025-05-01
Friedreich AtaxiaCardiomyopathy, Secondary

Gene Therapy for Cardiomyopathy Associated With Friedreich's Ataxia

ACTIVE NOT RECRUITING
NCT05445323Phase PHASE1, PHASE2Lexeo TherapeuticsStarted 2022-08-24
Low dose LX2006Mid Dose LX2006High Dose LX2006

External Resources

Links to major genomics databases and tools