CHCHD10

Chr 22AD

coiled-coil-helix-coiled-coil-helix domain containing 10

Also known as: C22orf16, FTDALS2, IMMD, MIX17A, N27C7-4, SMAJ

NCBI Gene: 400916ENSG00000250479UniProt: Q8WYQ3

This gene encodes a mitochondrial protein that is enriched at cristae junctions in the intermembrane space. It may play a role in cristae morphology maintenance or oxidative phosphorylation. Mutations in this gene cause frontotemporal dementia and/or amyotrophic lateral sclerosis-2. Alternative splicing of this gene results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 7 and 19. [provided by RefSeq, Aug 2014]

Primary Disease Associations & Inheritance

?Myopathy, isolated mitochondrial, autosomal dominantMIM #616209
AD
Frontotemporal dementia and/or amyotrophic lateral sclerosis 2MIM #615911
AD
Spinal muscular atrophy, Jokela typeMIM #615048
AD
397
ClinVar variants
65
Pathogenic / LP
0.00
pLI score
5
Active trials
Clinical Summary— CHCHD10
🧬
Gene-Disease Validity (ClinGen)
mitochondrial disease · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
65 Pathogenic / Likely Pathogenic· 195 VUS of 397 total submissions
💊
Clinical Trials
5 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.
1.91LOEUF
pLI 0.000
Z-score -0.75
OE 1.35 (0.73–1.91)
Tolerant

Highly tolerant — LoF variants common in population

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.
0.82Z-score
OE missense 0.71 (0.56–0.91)
47 obs / 65.8 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.1.35 (0.73–1.91)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.71 (0.56–0.91)
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.1.09
0≤1.21.6
LoF obs/exp: 7 / 5.2Missense obs/exp: 47 / 65.8Syn Z: -0.41

ClinVar Variant Classifications

397 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic52
Likely Pathogenic13
VUS195
Likely Benign107
Benign17
Conflicting13
52
Pathogenic
13
Likely Pathogenic
195
VUS
107
Likely Benign
17
Benign
13
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
4
48
0
52
Likely Pathogenic
0
2
11
0
13
VUS
7
110
74
4
195
Likely Benign
0
13
41
53
107
Benign
0
2
13
2
17
Conflicting
—13
Total713118759397

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

View in ClinVar →

Protein Context — Lollipop Plot

CHCHD10 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Myopathy, isolated mitochondrial, autosomal dominant

MIM #616209

Molecular basis of disorder known

Autosomal dominant

Frontotemporal dementia and/or amyotrophic lateral sclerosis 2

MIM #615911

Molecular basis of disorder known

Autosomal dominant

Spinal muscular atrophy, Jokela type

MIM #615048

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — CHCHD10
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications.
Chia R et al.·Lancet Neurol
2018Review
CHCHD2 and CHCHD10-related neurodegeneration: molecular pathogenesis and the path to precision therapy.
Shammas MK et al.·Biochem Soc Trans
2023Review
Mitochondria-associated programmed cell death: elucidating prognostic biomarkers, immune checkpoints, and therapeutic avenues in multiple myeloma.
Gao G et al.·Front Immunol
2024
Meta-analysis of the association between CHCHD10 Pro34Ser variant and the risk of amyotrophic lateral sclerosis.
Yang B et al.·Neurol Sci
2021Meta-analysis
Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism.
Harjuhaahto S et al.·Acta Neuropathol Commun
2025
Genetic and clinical landscape of Chinese frontotemporal dementia: dominance of TBK1 and OPTN mutations.
Nan H et al.·Alzheimers Res Ther
2024
Loss of CHCHD2 Stability Coordinates with C1QBP/CHCHD2/CHCHD10 Complex Impairment to Mediate PD-Linked Mitochondrial Dysfunction.
Ren YL et al.·Mol Neurobiol
2024
Genetics of frontotemporal dementia in China.
Jiang Y et al.·Amyotroph Lateral Scler Frontotemporal Degener
2021Review
Mutant CHCHD10 disrupts cytochrome c oxidation and activates mitochondrial retrograde signaling.
Campos-Ribeiro MA et al.·EMBO Mol Med
2026
Recent Updates on the Genetics of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.
Kirola L et al.·Mol Neurobiol
2022Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Amyotrophic Lateral Sclerosis

Personalized Antisense Oligonucleotide Therapy for A Single Participant With CHCHD10 ALS

ACTIVE NOT RECRUITING
NCT06392126Phase PHASE1, PHASE2n-Lorem FoundationStarted 2024-04-16
nL-CHCHD-001
Amyotrophic Lateral Sclerosis

Personalized Antisense Oligonucleotide for a Single Participant With CHCHD10 ALS

ACTIVE NOT RECRUITING
NCT06977451Phase PHASE1, PHASE2n-Lorem FoundationStarted 2024-06-24
nL-CHCHD-001
Neurodegenerative DiseasesDementia

Neurofilament Light Chain And Voice Acoustic Analyses In Dementia Diagnosis

RECRUITING
NCT06339190Monash UniversityStarted 2021-08-01
Venepuncture
Amyotrophic Lateral Sclerosis

Personalized Antisense Oligonucleotide for Participants With CHCHD10 ALS

ENROLLING BY INVITATION
NCT07095686Phase PHASE1, PHASE2n-Lorem FoundationStarted 2024-10-02
nL-CHCHD-001
Amyotrophic Lateral Sclerosis

Personalized Antisense Oligonucleotide Therapy for A Single Patient With CHCHD10 ALS (nL18576)

NOT YET RECRUITING
NCT07423494Phase PHASE1, PHASE2n-Lorem FoundationStarted 2026-03
nL-CHCHD-001

External Resources

Links to major genomics databases and tools