PHC1

Chr 12AR

polyhomeotic homolog 1

Also known as: EDR1, HPH1, MCPH11, RAE28

NCBI Gene: 1911 ENSG00000111752 UniProt: P78364 OMIM: 602978

The protein is a component of the Polycomb repressive complex that regulates gene expression through chromatin modification and contains conserved domains that mediate protein-protein interactions with other Polycomb group proteins. Loss-of-function mutations cause primary microcephaly 11, an autosomal recessive disorder characterized by reduced brain size. The high pLI score indicates this gene is highly intolerant to loss-of-function variants, consistent with haploinsufficiency being pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene is a homolog of the Drosophila polyhomeotic gene, which is a member of the Polycomb group of genes. The gene product is a component of a multimeric protein complex that contains EDR2 and the vertebrate Polycomb protein BMH1. The gene product, the EDR2 protein, and the Drosophila polyhomeotic protein share 2 highly conserved domains, named homology domains I and II. These domains are involved in protein-protein interactions and may mediate heterodimerization of the protein encoded by this gene and the EDR2 protein. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.241 OMIM phenotype

Clinical Summary— PHC1

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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

2 unique Pathogenic / Likely Pathogenic· 143 VUS of 199 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.24LOEUF

pLI 0.999

Z-score 5.40

OE 0.12 (0.06–0.24)

Highly constrained

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

Missense Constraint?

1.92Z-score

OE missense 0.76 (0.69–0.82)

375 obs / 495.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.12 (0.06–0.24)

0≤0.351.4

Missense OE?0.76 (0.69–0.82)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 5 / 43.3Missense obs/exp: 375 / 495.1Syn Z: -0.12

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedPHC1-related primary microcephalyOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.2897th %ile

GOF

0.2796th %ile

LOF

0.80top 5%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

199 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic1

VUS143

Likely Benign18

Benign27

Pathogenic

Likely Pathogenic

143

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	0	1
Likely Pathogenic	0	1	0	0	1
VUS	0	141	1	1	143
Likely Benign	1	4	2	11	18
Benign	0	4	19	4	27
Total	2	150	22	16	190

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

View in ClinVar →

37 pathogenic / likely-pathogenic (of 43) ClinVar copy-number / structural variants overlap PHC1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →