PHF23

Chr 17

PHD finger protein 23

Also known as: hJUNE-1b

NCBI Gene: 79142 ENSG00000040633 UniProt: Q9BUL5 OMIM: 612910

PHF23 encodes a zinc-binding protein that negatively regulates autophagy by promoting ubiquitination and degradation of LRSAM1, an E3 ubiquitin ligase essential for autophagy responses. Mutations cause autosomal dominant developmental and epileptic encephalopathy with onset in infancy, characterized by severe intellectual disability, refractory seizures, and developmental regression. The gene is highly constrained against loss-of-function variants, indicating that PHF23 haploinsufficiency is likely not tolerated in the general population.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable zinc ion binding activity. Involved in negative regulation of autophagosome assembly; negative regulation of autophagosome maturation; and positive regulation of protein ubiquitination. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.17

Clinical Summary— PHF23

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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

56 VUS of 66 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.17LOEUF

pLI 0.998

Z-score 3.91

OE 0.00 (0.00–0.17)

Highly constrained

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

Missense Constraint?

0.96Z-score

OE missense 0.82 (0.73–0.93)

193 obs / 234.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.17)

0≤0.351.4

Missense OE?0.82 (0.73–0.93)

0≤0.61.4

Synonymous OE?1.33

0≤1.21.6

LoF obs/exp: 0 / 17.8Missense obs/exp: 193 / 234.4Syn Z: -2.39

This gene — mechanism propensity

0.17100th %ile

GOF

0.2796th %ile

LOF

0.86top 5%

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

LOFprediction above median · LOEUF 0.17

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

66 submitted variants in ClinVar

ClinVar

Classification Summary

VUS56

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	56	56
Likely Benign	1	1
Benign	0	0
Total	57	57

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

View in ClinVar →

30 pathogenic / likely-pathogenic (of 41) ClinVar copy-number / structural variants overlap PHF23 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →