CHCHD3

Chr 7

coiled-coil-helix-coiled-coil-helix domain containing 3

Also known as: MICOS19, MINOS3, Mic19, PPP1R22

NCBI Gene: 54927ENSG00000106554UniProt: Q9NX63

The protein encoded by this gene is an inner mitochondrial membrane scaffold protein. Absence of the encoded protein affects the structural integrity of mitochondrial cristae and leads to reductions in ATP production, cell growth, and oxygen consumption. This protein is part of the mitochondrial contact site and cristae organizing system (MICOS). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2015]

0
Active trials
32
Pathogenic / LP
73
ClinVar variants
6
Pubs (1 yr)
0.4
Missense Z
0.64
LOEUF
Clinical Summary— CHCHD3
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.
📋
ClinVar Variants
32 Pathogenic / Likely Pathogenic· 41 VUS of 73 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
0.64LOEUF
pLI 0.028
Z-score 2.69
OE 0.32 (0.18–0.64)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
0.37Z-score
OE missense 0.91 (0.78–1.06)
114 obs / 125.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.32 (0.18–0.64)
0≤0.351.4
Missense OE0.91 (0.78–1.06)
0≤0.61.4
Synonymous OE0.87
0≤1.21.6
LoF obs/exp: 6 / 18.5Missense obs/exp: 114 / 125.6Syn Z: 0.67
DNGOF
DN
0.88top 5%
GOF
0.6344th %ile
LOF
0.1895th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median
GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

73 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic31
Likely Pathogenic1
VUS41
31
Pathogenic
1
Likely Pathogenic
41
VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
31
0
31
Likely Pathogenic
0
0
1
0
1
VUS
0
33
8
0
41
Likely Benign
0
0
0
0
0
Benign
0
0
0
0
0
Total03340073

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

View in ClinVar →

CHCHD3 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Loss of MTX2 causes mitochondrial dysfunction, podocyte injury, nephrotic proteinuria and glomerulopathy in mice and patients.
Li T et al.·Int J Biol Sci
2024Cohort
Mitochondrial MICOS complex genes, implicated in hypoplastic left heart syndrome, maintain cardiac contractility and actomyosin integrity.
Birker K et al.·Elife
2023
PD-1 signaling affects cristae morphology and leads to mitochondrial dysfunction in human CD8(+) T lymphocytes.
Ogando J et al.·J Immunother Cancer
2019
CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis.
Genin EC et al.·EMBO Mol Med
2016
Detection of targetable genetic alterations in SMARCA4-deficient neoplasms of the lung - further evidence of a relationship between SMARCA4-deficient undifferentiated tumor and non-small cell carcinoma.
D'Ambrosio D et al.·Hum Pathol
2026
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients