DGCR6

Chr 22

DiGeorge syndrome critical region gene 6

NCBI Gene: 8214 ENSG00000183628 UniProt: Q14129 OMIM: 601279

The DGCR6 protein may function in neural crest cell migration into the third and fourth pharyngeal pouches during embryonic development. Mutations cause DiGeorge syndrome as part of 22q11.2 deletion syndrome, which affects multiple systems including cardiac, immune, parathyroid, and neuropsychiatric functions. This gene shows extremely high constraint against loss-of-function variants (pLI ~1.0) and is associated with autosomal dominant inheritance as part of the 22q11.2 microdeletion.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

DiGeorge syndrome, and more widely, the CATCH 22 syndrome, are associated with microdeletions in chromosomal region 22q11.2. The product of this gene shares homology with the Drosophila melanogaster gonadal protein, which participates in gonadal and germ cell development, and with the gamma-1 subunit of human laminin. This gene is a candidate for involvement in DiGeorge syndrome pathology and in schizophrenia. [provided by RefSeq, Nov 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.83

Clinical Summary— DGCR6

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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· 50 VUS of 65 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — DGCR6

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.83LOEUF

pLI 0.000

Z-score -0.88

OE 1.28 (0.85–1.83)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.14Z-score

OE missense 1.03 (0.90–1.20)

130 obs / 125.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.28 (0.85–1.83)

0≤0.351.4

Missense OE?1.03 (0.90–1.20)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 15 / 11.8Missense obs/exp: 130 / 125.7Syn Z: -0.74

This gene — mechanism propensity

0.6161th %ile

GOF

0.74top 25%

LOF

0.3745th %ile

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

GOFprediction above median

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

65 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic1

VUS50

Likely Benign5

Benign2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	1
Likely Pathogenic	0	1	0	1
VUS	48	2	0	50
Likely Benign	2	0	3	5
Benign	0	1	1	2
Total	50	5	4	59

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

View in ClinVar →

307 pathogenic / likely-pathogenic (of 341) ClinVar copy-number / structural variants overlap DGCR6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →