POT1

Chr 7ARAD

protection of telomeres 1

Also known as: CMM10, CRMCC3, GLM9, HPOT1, PFBMFT8, TPDS3

NCBI Gene: 25913ENSG00000128513UniProt: Q9NUX5

This gene is a member of the telombin family and encodes a nuclear protein involved in telomere maintenance. Specifically, this protein functions as a member of a multi-protein complex that binds to the TTAGGG repeats of telomeres, regulating telomere length and protecting chromosome ends from illegitimate recombination, catastrophic chromosome instability, and abnormal chromosome segregation. Increased transcriptional expression of this gene is associated with stomach carcinogenesis and its progression. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

?Cerebroretinal microangiopathy with calcifications and cysts 3MIM #620368
AR
?Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8MIM #620367
AD
Tumor predisposition syndrome 3MIM #615848
AD
583
ClinVar variants
51
Pathogenic / LP
0.85
pLI score
2
Active trials
Clinical Summary— POT1
🧬
Gene-Disease Validity (ClinGen)
tumor predisposition syndrome 3 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.85) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
51 Pathogenic / Likely Pathogenic· 339 VUS of 583 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.36LOEUF
pLI 0.853
Z-score 4.33
OE 0.18 (0.10–0.36)
Moderately constrained

More LoF-intolerant than ~75% of genes

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.
1.92Z-score
OE missense 0.70 (0.63–0.78)
226 obs / 323.4 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.0.18 (0.10–0.36)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.70 (0.63–0.78)
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.1.09
0≤1.21.6
LoF obs/exp: 6 / 32.7Missense obs/exp: 226 / 323.4Syn Z: -0.76

ClinVar Variant Classifications

583 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic36
Likely Pathogenic15
VUS339
Likely Benign186
Benign1
Conflicting6
36
Pathogenic
15
Likely Pathogenic
339
VUS
186
Likely Benign
1
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
17
0
19
0
36
Likely Pathogenic
11
2
2
0
15
VUS
9
293
31
6
339
Likely Benign
0
9
96
81
186
Benign
0
0
1
0
1
Conflicting
—6
Total3730414987583

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

View in ClinVar →

Protein Context — Lollipop Plot

POT1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

POT1-related Coats plus

limited
ARUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Cerebroretinal microangiopathy with calcifications and cysts 3

MIM #620368

Molecular basis of disorder known

Autosomal recessive

?Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8

MIM #620367

Molecular basis of disorder known

Autosomal dominant

Tumor predisposition syndrome 3

MIM #615848

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — POT1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Germline mutations predisposing to melanoma.
Toussi A et al.·J Cutan Pathol
2020Review
Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in Patients With Osteosarcoma.
Mirabello L et al.·JAMA Oncol
2020Cohort
Familial Clonal Hematopoiesis in a Long Telomere Syndrome.
DeBoy EA et al.·N Engl J Med
2023
Melanoma Genomics.
Newton-Bishop J et al.·Acta Derm Venereol
2020Review
Clonal landscape and clinical outcomes of telomere biology disorders: somatic rescue and cancer mutations.
Gutierrez-Rodrigues F et al.·Blood
2024
Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles.
Kim E et al.·Cancer Discov
2016Functional
Germline POT1 Variants: A Critical Perspective on POT1 Tumor Predisposition Syndrome.
Andreotti V et al.·Genes (Basel)
2024Review
A POT1 Founder Variant Associated with Early Onset Recurrent Melanoma and Various Solid Malignancies.
Abu Shtaya A et al.·Genes (Basel)
2024Review
The evolving genetic landscape of telomere biology disorder dyskeratosis congenita.
Tummala H et al.·EMBO Mol Med
2024
UK clinical practice guidelines for the management of patients with constitutional POT1 pathogenic variants.
Tsoulaki O et al.·J Med Genet
2025Guideline
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
Uveal Melanoma

Identification of New Candidate Genes for Hereditary Predisposition to Uveal Melanoma

ACTIVE NOT RECRUITING
NCT06550674Phase NACentre Jean PerrinStarted 2024-10-29
Constitutional exome analysis
Kidney Disease, ChronicKidney Failure Chronic

Physical Exercise and Biomolecular Analysis to Reduce Uremic Toxins in Chronic Kidney Disease: An Exploratory Study

NOT YET RECRUITING
NCT06910475Phase NACatholic University of BrasíliaStarted 2025-04-01
Resistance trainingEndurance trainingConcurrent training

External Resources

Links to major genomics databases and tools