CHCHD6

Chr 3

coiled-coil-helix-coiled-coil-helix domain containing 6

Also known as: CHCM1, MICOS25, Mic25, PPP1R23

NCBI Gene: 84303 ENSG00000159685 UniProt: Q9BRQ6 OMIM: 615634

The CHCHD6 protein is a component of the MICOS complex that maintains mitochondrial inner membrane architecture and crista junctions. Mutations cause autosomal recessive mitochondrial complex IV deficiency presenting in infancy with severe neurodegeneration, developmental delay, and early lethality. This gene shows low constraint against loss-of-function variants.

OMIM ResearchSummary from RefSeq, UniProt

Involved in DNA damage response and cristae formation. Located in cytosol and mitochondrial inner membrane. Part of MICOS complex. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.52

Clinical Summary— CHCHD6

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

37 VUS of 50 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.52LOEUF

pLI 0.000

Z-score 0.14

OE 0.96 (0.62–1.52)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.62Z-score

OE missense 1.15 (1.01–1.31)

160 obs / 139.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.96 (0.62–1.52)

0≤0.351.4

Missense OE?1.15 (1.01–1.31)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 13 / 13.5Missense obs/exp: 160 / 139.5Syn Z: -0.31

This gene — mechanism propensity

0.78top 25%

GOF

0.4875th %ile

LOF

0.3066th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction 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

50 submitted variants in ClinVar

ClinVar

Classification Summary

VUS37

Likely Benign6

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	37	0	37
Likely Benign	5	1	6
Benign	0	1	1
Total	42	2	44

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap CHCHD6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →