PCGF2

Chr 17

polycomb group ring finger 2

Also known as: MEL-18, RNF110, TPFS, ZNF144

NCBI Gene: 7703 ENSG00000277258 UniProt: P35227

The protein is a transcriptional repressor that functions as a component of Polycomb repressive complex 1 (PRC1), maintaining transcriptional silencing of developmental genes including Hox genes through chromatin modification. Mutations cause Turnpenny-Fry syndrome with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 0.86, LOEUF 0.41), indicating intolerance to gene disruption.

ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene contains a RING finger motif and is similar to the polycomb group (PcG) gene products. PcG gene products form complexes via protein-protein interaction and maintain the transcription repression of genes involved in embryogenesis, cell cycles, and tumorigenesis. This protein was shown to act as a negative regulator of transcription and has tumor suppressor activity. The expression of this gene was detected in various tumor cells, but is limited in neural organs in normal tissues. Knockout studies in mice suggested that this protein may negatively regulate the expression of different cytokines, chemokines, and chemokine receptors, and thus plays an important role in lymphocyte differentiation and migration, as well as in immune responses. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.41

Clinical Summary— PCGF2

🧬

Gene-Disease Validity (ClinGen)

turnpenny-fry syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.86) — some intolerance to loss-of-function variants.

📋

ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 139 VUS of 331 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.41LOEUF

pLI 0.864

Z-score 3.15

OE 0.13 (0.05–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.95Z-score

OE missense 0.81 (0.72–0.93)

169 obs / 207.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.13 (0.05–0.41)

0≤0.351.4

Missense OE?0.81 (0.72–0.93)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 2 / 15.3Missense obs/exp: 169 / 207.6Syn Z: -0.35

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongPCGF2-related craniofacial neurological cardiovascular and skeletal features (Turnpenny-Fry syndrome)GOFAD

This gene — mechanism propensity

0.4487th %ile

GOF

0.4480th %ile

LOF

0.70top 10%

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 · LOEUF 0.41

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

DNMutant PCGF2 may have dominant-negative effects, sequestering PRC1 components into complexes that lack the ability to interact efficiently with histones.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 30343942 ↗

ClinVar Variant Classifications

331 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic3

VUS139

Likely Benign131

Benign25

Conflicting15

Likely Pathogenic

139

VUS

131

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	0	0	0
Likely Pathogenic	0	3	0	0	3
VUS	12	121	5	1	139
Likely Benign	0	16	47	68	131
Benign	0	8	11	6	25
Conflicting	—				15
Total	12	148	63	75	313

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

View in ClinVar →

7 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap PCGF2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →