CRTC3

Chr 15

CREB regulated transcription coactivator 3

Also known as: TORC-3, TORC3

NCBI Gene: 64784 ENSG00000140577 UniProt: Q6UUV7 OMIM: 608986

The CRTC3 protein functions as a transcriptional coactivator for CREB1, activating cAMP-responsive genes and inducing mitochondrial biogenesis in muscle cells. This gene is highly constrained against loss-of-function variants (pLI=0.87, LOEUF=0.36), but no Mendelian diseases have been definitively associated with CRTC3 mutations in current databases. While chromosomal translocations involving CRTC3 have been reported in mucoepidermoid carcinomas, germline variants causing pediatric neurological disorders have not been established.

OMIM ResearchSummary from RefSeq, UniProt

This gene is a member of the CREB regulated transcription coactivator gene family. This family regulates CREB-dependent gene transcription in a phosphorylation-independent manner and may be selective for cAMP-responsive genes. The protein encoded by this gene may induce mitochondrial biogenesis and attenuate catecholamine signaling in adipose tissue. A translocation event between this gene and Notch coactivator mastermind-like gene 2, which results in a fusion protein, has been reported in mucoepidermoid carcinomas. Alternative splicing results in multiple transcript variants that encode different protein isoforms. [provided by RefSeq, Jul 2012]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.36

Clinical Summary— CRTC3

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.87) — some intolerance to loss-of-function variants.

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ClinVar Variants

80 VUS of 102 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.36LOEUF

pLI 0.866

Z-score 4.35

OE 0.18 (0.10–0.36)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.40Z-score

OE missense 0.94 (0.86–1.03)

327 obs / 348.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.18 (0.10–0.36)

0≤0.351.4

Missense OE?0.94 (0.86–1.03)

0≤0.61.4

Synonymous OE?1.26

0≤1.21.6

LoF obs/exp: 6 / 33.0Missense obs/exp: 327 / 348.0Syn Z: -2.43

This gene — mechanism propensity

0.4983th %ile

GOF

0.3788th %ile

LOF

0.75top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.36

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

102 submitted variants in ClinVar

ClinVar

Classification Summary

VUS80

Likely Benign5

Benign2

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	80	0	80
Likely Benign	4	1	5
Benign	0	2	2
Total	84	3	87

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

View in ClinVar →

41 pathogenic / likely-pathogenic (of 46) ClinVar copy-number / structural variants overlap CRTC3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →