HPDL

Chr 1AR

programmed cell death 1

Also known as: ADMIO4, AIMTBS, CD279, PD-1, PD1, SLEB2, hPD-1, hPD-l

NCBI Gene: 5133ENSG00000186603UniProt: Q96IR7

Programmed cell death protein 1 (PDCD1) is an immune-inhibitory receptor expressed in activated T cells; it is involved in the regulation of T-cell functions, including those of effector CD8+ T cells. In addition, this protein can also promote the differentiation of CD4+ T cells into T regulatory cells. PDCD1 is expressed in many types of tumors including melanomas, and has demonstrated to play a role in anti-tumor immunity. Moreover, this protein has been shown to be involved in safeguarding against autoimmunity, however, it can also contribute to the inhibition of effective anti-tumor and anti-microbial immunity. [provided by RefSeq, Aug 2020]

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalitiesMIM #619026
AR
Spastic paraplegia 83, autosomal recessiveMIM #619027
AR
144
ClinVar variants
58
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— HPDL
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
58 Pathogenic / Likely Pathogenic· 69 VUS of 144 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
1.43LOEUF
pLI 0.000
Z-score 0.59
OE 0.80 (0.47–1.43)
Tolerant

Highly tolerant — LoF variants common in population

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.
0.93Z-score
OE missense 0.83 (0.74–0.93)
197 obs / 237.5 exp
Tolerant

Mild missense constraint

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.0.80 (0.47–1.43)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.83 (0.74–0.93)
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.0.86
0≤1.21.6
LoF obs/exp: 8 / 10.0Missense obs/exp: 197 / 237.5Syn Z: 1.21

ClinVar Variant Classifications

144 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21
Likely Pathogenic37
VUS69
Likely Benign9
Benign3
Conflicting4
21
Pathogenic
37
Likely Pathogenic
69
VUS
9
Likely Benign
3
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
6
9
0
21
Likely Pathogenic
12
18
7
0
37
VUS
1
58
10
0
69
Likely Benign
0
7
0
2
9
Benign
0
0
1
2
3
Conflicting
—4
Total1989274143

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

View in ClinVar →

Protein Context — Lollipop Plot

HPDL · protein map & ClinVar variants

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

Gene2Phenotype Curations

HPDL-related neurodegenerative disease

strong
ARLoss 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

Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities

MIM #619026

Molecular basis of disorder known

Autosomal recessive

Spastic paraplegia 83, autosomal recessive

MIM #619027

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Novel lactylation-related signature to predict prognosis for pancreatic adenocarcinoma.
Peng T et al.·World J Gastroenterol
2024
HPDL Variant Type Correlates With Clinical Disease Onset and Severity.
Lee EH et al.·Ann Clin Transl Neurol
2025
A novel homozygous HPDL variant in Japanese siblings with autosomal recessive hereditary spastic paraplegia: case report and literature review.
Kojima F et al.·Neurogenetics
2024Review
HPDL mutations identified by exome sequencing are associated with infant neurodevelopmental disorders.
Wang Y et al.·Mol Genet Genomic Med
2022
Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia.
Wiessner M et al.·Brain
2021
Bi-allelic HPDL Variants Cause a Neurodegenerative Disease Ranging from Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia.
Husain RA et al.·Am J Hum Genet
2020
HPDL deficiency causes a neuromuscular disease by impairing the mitochondrial respiration.
Sun Y et al.·J Genet Genomics
2021
Genotype variability in early-onset Hereditary Spastic Paraplegia: a single-center study.
Colona VL et al.·Eur J Paediatr Neurol
2025
Transient global amnesia with unexpected clinical and radiological findings: A case series and systematic review.
Piffer S et al.·J Neurol Sci
2022Review
Phytic acid effect on periodontal ligament fibroblast: An in-vitro study.
Aryal A C S et al.·PLoS One
2023
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools