DPF2

Chr 11AD

double PHD fingers 2

Also known as: CSS7, REQ, SMARCG2, UBID4, ubi-d4

NCBI Gene: 5977 ENSG00000133884 UniProt: Q92785 OMIM: 601671

DPF2 encodes a transcription factor containing a zinc finger-like structural motif that regulates apoptotic responses following deprivation of survival factors and plays a role in hematopoietic cell growth and turnover. Loss-of-function mutations cause Coffin-Siris syndrome 7, a neurodevelopmental disorder inherited in an autosomal dominant pattern. The gene is highly intolerant to loss-of-function variants, consistent with haploinsufficiency as the pathogenic mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene is a member of the d4 domain family, characterized by a zinc finger-like structural motif. This protein functions as a transcription factor which is necessary for the apoptotic response following deprivation of survival factors. It likely serves a regulatory role in rapid hematopoietic cell growth and turnover. This gene is considered a candidate gene for multiple endocrine neoplasia type I, an inherited cancer syndrome involving multiple parathyroid, enteropancreatic, and pituitary tumors. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismADLOEUF 0.161 OMIM phenotype

Clinical Summary— DPF2

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Gene-Disease Validity (ClinGen)

Coffin-Siris syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

19 unique Pathogenic / Likely Pathogenic· 106 VUS of 276 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — DPF2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.16LOEUF

pLI 1.000

Z-score 4.86

OE 0.03 (0.01–0.16)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.90Z-score

OE missense 0.48 (0.41–0.56)

117 obs / 244.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.03 (0.01–0.16)

0≤0.351.4

Missense OE?0.48 (0.41–0.56)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 1 / 29.4Missense obs/exp: 117 / 244.5Syn Z: -0.24

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongDPF2-related Coffin-Siris like disorderDNAD

This gene — mechanism propensity

0.3296th %ile

GOF

0.3193th %ile

LOF

0.79top 5%

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

LOFprediction above median · 32% of P/LP variants are LoF · LOEUF 0.16

DN1 literature citation

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.

Literature Evidence

DNAltogether, we provide compelling evidence that de novo variants in DPF2 cause Coffin-Siris syndrome and propose a dominant-negative mechanism of pathogenicity.1

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

References

1.PMID 29429572 ↗

ClinVar Variant Classifications

276 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8

Likely Pathogenic11

VUS106

Likely Benign112

Benign13

Conflicting13

Pathogenic

Likely Pathogenic

106

VUS

112

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	5	0	0	8
Likely Pathogenic	3	8	0	0	11
VUS	5	94	3	4	106
Likely Benign	1	8	53	50	112
Benign	0	3	7	3	13
Conflicting	—				13
Total	12	118	63	57	263

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap DPF2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →