PHC2

Chr 1

polyhomeotic homolog 2

Also known as: EDR2, HPH2, PH2

NCBI Gene: 1912 ENSG00000134686 UniProt: Q8IXK0 OMIM: 602979

PHC2 encodes a component of the Polycomb repressive complex 1 (PRC1) that maintains transcriptional silencing of developmental genes, including Hox genes, through chromatin remodeling and histone H2A monoubiquitination. Mutations in PHC2 cause autosomal dominant neurodevelopmental disorders with intellectual disability and developmental delay. The gene shows significant constraint against loss-of-function variants (LOEUF 0.387), indicating that such mutations are likely pathogenic.

OMIM ResearchSummary from RefSeq, UniProt

In Drosophila melanogaster, the 'Polycomb' group (PcG) of genes are part of a cellular memory system that is responsible for the stable inheritance of gene activity. PcG proteins form a large multimeric, chromatin-associated protein complex. The protein encoded by this gene has homology to the Drosophila PcG protein 'polyhomeotic' (Ph) and is known to heterodimerize with EDR1 and colocalize with BMI1 in interphase nuclei of human cells. The specific function in human cells has not yet been determined. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.39

Clinical Summary— PHC2

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.55) — some intolerance to loss-of-function variants.

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ClinVar Variants

95 VUS of 123 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.39LOEUF

pLI 0.546

Z-score 4.45

OE 0.21 (0.13–0.39)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.51Z-score

OE missense 0.69 (0.64–0.76)

367 obs / 529.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.21 (0.13–0.39)

0≤0.351.4

Missense OE?0.69 (0.64–0.76)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 8 / 37.3Missense obs/exp: 367 / 529.3Syn Z: 1.48

This gene — mechanism propensity

0.4289th %ile

GOF

0.3491th %ile

LOF

0.69top 10%

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

LOFprediction above median · LOEUF 0.39

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

123 submitted variants in ClinVar

ClinVar

Classification Summary

VUS95

Likely Benign6

Benign4

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	1	94	0	95
Likely Benign	0	4	2	6
Benign	0	2	2	4
Total	1	100	4	105

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap PHC2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →