PHF21A

Chr 11AD

PHD finger protein 21A

Also known as: BHC80, BM-006, IDDBCS, NEDMS

NCBI Gene: 51317ENSG00000135365UniProt: Q96BD5

The PHF21A gene encodes BHC80, a component of a BRAF35 (MIM 605535)/histone deacetylase (HDAC; see MIM 601241) complex (BHC) that mediates repression of neuron-specific genes through the cis-regulatory element known as repressor element-1 (RE1) or neural restrictive silencer (NRS) (Hakimi et al., 2002 [PubMed 12032298]).[supplied by OMIM, Nov 2010]

Primary Disease Associations & Inheritance

Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizuresMIM #618725
AD
401
ClinVar variants
59
Pathogenic / LP
1.00
pLI score· haploinsufficient
1
Active trials
Clinical Summary— PHF21A
🧬
Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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.
📋
ClinVar Variants
59 Pathogenic / Likely Pathogenic· 167 VUS of 401 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.08LOEUF
pLI 1.000
Z-score 5.64
OE 0.00 (0.00–0.08)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.86Z-score
OE missense 0.59 (0.53–0.66)
223 obs / 379.9 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.08)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.59 (0.53–0.66)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.88
0≤1.21.6
LoF obs/exp: 0 / 37.1Missense obs/exp: 223 / 379.9Syn Z: 1.17

ClinVar Variant Classifications

401 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic42
Likely Pathogenic17
VUS167
Likely Benign121
Benign38
Conflicting16
42
Pathogenic
17
Likely Pathogenic
167
VUS
121
Likely Benign
38
Benign
16
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
16
1
25
0
42
Likely Pathogenic
11
0
6
0
17
VUS
5
142
19
1
167
Likely Benign
1
12
42
66
121
Benign
0
16
14
8
38
Conflicting
—16
Total3317110675401

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

View in ClinVar →

Protein Context — Lollipop Plot

PHF21A · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

PHF21A-related Potocki-Shaffer syndrome

strong
ADLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures

MIM #618725

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
[A case of intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures caused by PHF21A gene variation and review of literature].
Wu F et al.·Zhonghua Er Ke Za Zhi
2023Review
De novo variants in PHF21A cause intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures: A case report and literature review.
Chen H et al.·Seizure
2023Review
PHF21A expression as a biomarker of hepatocellular carcinoma progression and prognosis.
Huang JQ et al.·Neoplasma
2022
Disruption of PHF21A causes syndromic intellectual disability with craniofacial anomalies, epilepsy, hypotonia, and neurobehavioral problems including autism.
Kim HG et al.·Mol Autism
2019Case report
The PHF21A neurodevelopmental disorder: an evaluation of clinical data from 13 patients.
Poole RL et al.·Clin Dysmorphol
2023Cohort
A novel de novo variant in the PHF21A causes craniofacial abnormalities, intellectual disability and skeletal manifestations.
Mustafa S et al.·Clin Genet
2023
A zebrafish model unravels the role of PHF21A in neurodevelopment and epilepsy.
Wang T et al.·Neuroscience
2025Functional
PHF21A Related Disorder: Description of a New Case.
Butera A et al.·Int J Mol Sci
2022Case report
Molecular Consequences of a Missense PHF21A Variant, c.1285G > A, Associated With Syndromic Neurodevelopmental Disorder.
Gavilan CM et al.·Cell Mol Neurobiol
2025
De novo truncating variants in PHF21A cause intellectual disability and craniofacial anomalies.
Hamanaka K et al.·Eur J Hum Genet
2019Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10

External Resources

Links to major genomics databases and tools