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…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.36

LOEUF

LOF

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in CRTC3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 74

820 rare PASS variants

Rare truncating (LoF)

1 in 1,300

58 rare PASS variants

Rare synonymous (reference)

1 in 92

401 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CRTC3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 75	1 in 3,500
South Asian	~43k	1 in 64	1 in 5,100
Remaining (unassigned)	~30k	1 in 67	1 in 1,700
European (Finnish)	~27k	1 in 390	1 in 2,600
Admixed American	~22k	1 in 73	1 in 3,800
African / African American	~21k	1 in 55	1 in 3,600
East Asian	~20k	1 in 80	1 in 1,100
Ashkenazi Jewish	~13k	1 in 430	1 in 2,600
Middle Eastern	~2,884	1 in 77	≈ 1 in 1,200

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 10 of 15 coding exons well covered in gnomAD exomes; exons 1, 4, 6, 7, 8 marginal. Genomes: all 15.? see exons ↓