ATAD3C

Chr 1

ATPase family AAA domain containing 3C

NCBI Gene: 219293 ENSG00000215915 UniProt: Q5T2N8 OMIM: 617227

The ATAD3C protein is an ATPase that hydrolyzes ATP and is involved in mitochondrial organization. Mutations cause autosomal recessive developmental and epileptic encephalopathy with microcephaly, typically presenting in infancy. This gene shows very low constraint against loss-of-function variants, consistent with recessive inheritance where heterozygous carriers are unaffected.

OMIM ResearchSummary from RefSeq

Predicted to enable ATP binding activity and ATP hydrolysis activity. Predicted to be involved in mitochondrion organization. Located in mitochondrion. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.17

Clinical Summary— ATAD3C

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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

2 unique Pathogenic / Likely Pathogenic· 112 VUS of 145 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.17LOEUF

pLI 0.000

Z-score 0.98

OE 0.76 (0.51–1.17)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.82Z-score

OE missense 1.14 (1.04–1.25)

302 obs / 264.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.76 (0.51–1.17)

0≤0.351.4

Missense OE?1.14 (1.04–1.25)

0≤0.61.4

Synonymous OE?1.17

0≤1.21.6

LoF obs/exp: 15 / 19.7Missense obs/exp: 302 / 264.7Syn Z: -1.40

This gene — mechanism propensity

0.79top 25%

GOF

0.6443th %ile

LOF

0.2484th %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

145 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

VUS112

Likely Benign12

Benign1

Conflicting1

Pathogenic

112

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	2	0	2
Likely Pathogenic	0	0	0	0	0
VUS	0	111	1	0	112
Likely Benign	0	9	2	1	12
Benign	0	1	0	0	1
Conflicting	—				1
Total	0	121	5	1	128

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

View in ClinVar →

131 pathogenic / likely-pathogenic (of 165) ClinVar copy-number / structural variants overlap ATAD3C — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →