# NM_015450.3(POT1):c.693A>T (p.Arg231Ser)

https://sugi.bio/variant/pot1-p-arg231ser

## Summary

**POT1 p.Arg231Ser (c.693A>T)** is classified **Uncertain significance** in POT1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-22). AlphaMissense: likely benign (0.2284); Very rare (popmax 8.51e-05%, nfe); Associated with tumor predisposition syndrome 3.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1795514618 · 3 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 8.51e-05%, nfe)

## For patients & families {#patients}

This is a change in the POT1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to tumor predisposition syndrome 3.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018582/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [POT1](https://sugi.bio/atlas/gene/POT1/) |
| Protein change (HGVS p.) | p.Arg231Ser |
| Coding change (HGVS c.) | c.693A>T |
| MANE Select transcript | [NM_015450](https://www.ncbi.nlm.nih.gov/nuccore/NM_015450) |
| dbSNP | [rs1795514618](https://www.ncbi.nlm.nih.gov/snp/rs1795514618/) |
| Variant type | single nucleotide variant |
| Location | chr7:124858966-124858966 (GRCh38) |
| ClinVar | [VCV950918](https://www.ncbi.nlm.nih.gov/clinvar/variation/950918/) |

**All HGVS expressions:** `NC_000007.13:g.124499020T>A`, `NC_000007.14:g.124858966T>A`, `NG_029232.1:g.76018A>T`, `NM_001042594.2:c.300A>T`, `NM_015450.3:c.693A>T`, `NR_003102.2:n.1136A>T`, `NR_003103.2:n.1136A>T`, `NR_003104.2:n.1136A>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.2284)
- REVEL 0.021 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.863 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.20) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 0.451, GERP -3.68, phastCons 0.982 — weakly conserved position
- CADD: **PHRED 19.65**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.74** across the covering region of the MANE Select transcript (124,852,986–124,897,173), spanning 44,187 bp. Chi-square p 1.3e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.20**, acceptor gain **0.00**, donor gain **0.01**. Largest is donor loss, 9 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.01**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **8.51e-05%** (nfe) · 1/1,174,402 in the highest group · 1/1,605,018 alleles overall — very rare (popmax 8.51e-05%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**POT1** population constraint: LOEUF 0.871, pLI 3.5567e-05, missense-Z 1.6079; ClinGen dosage — haploinsufficiency 2/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **tumor predisposition syndrome 3** — Definitive (AD)

## Protein context {#protein}

Residue **231** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 87.63, 69% of residues very-high.

**14 experimental structure(s)** (PDB): [1XJV](https://www.rcsb.org/structure/1XJV), [3KJO](https://www.rcsb.org/structure/3KJO), [3KJP](https://www.rcsb.org/structure/3KJP), [5H65](https://www.rcsb.org/structure/5H65), [5UN7](https://www.rcsb.org/structure/5UN7), [7QXB](https://www.rcsb.org/structure/7QXB).

## What this gene does {#gene-function}

*Describes the biological roles of POT1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** POT1's established molecular role includes telomerase inhibitor activity.


### Pathways affected {#pathways}

POT1 participates in **14 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [DNA Damage/Telomere Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559586) | curated |
| [Inhibition of DNA recombination at telomere](https://reactome.org/content/detail/R-HSA-9670095) | curated |
| [Packaging Of Telomere Ends](https://reactome.org/content/detail/R-HSA-171306) | curated |
| [Polymerase switching on the C-strand of the telomere](https://reactome.org/content/detail/R-HSA-174411) | curated |
| [Processive synthesis on the C-strand of the telomere](https://reactome.org/content/detail/R-HSA-174414) | curated |
| [Removal of the Flap Intermediate from the C-strand](https://reactome.org/content/detail/R-HSA-174437) | curated |
| [Telomere C-strand (Lagging Strand) Synthesis](https://reactome.org/content/detail/R-HSA-174417) | curated |
| [Telomere C-strand synthesis initiation](https://reactome.org/content/detail/R-HSA-174430) | curated |
| [Telomere Extension By Telomerase](https://reactome.org/content/detail/R-HSA-171319) | curated |
| [Cleavage of the damaged purine](https://reactome.org/content/detail/R-HSA-110331) | electronic |
| [Cleavage of the damaged pyrimidine ](https://reactome.org/content/detail/R-HSA-110329) | electronic |
| [Meiotic synapsis](https://reactome.org/content/detail/R-HSA-1221632) | electronic |
| [Recognition and association of DNA glycosylase with site containing an affected purine](https://reactome.org/content/detail/R-HSA-110330) | electronic |
| [Recognition and association of DNA glycosylase with site containing an affected pyrimidine](https://reactome.org/content/detail/R-HSA-110328) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** telomerase inhibitor activity, DEAD/H-box RNA helicase binding, telomeric repeat DNA binding, single-stranded telomeric DNA binding, telomeric D-loop binding, G-rich strand telomeric DNA binding.

**Biological process:** telomere maintenance via telomerase, telomere capping, telomere assembly, regulation of telomere maintenance via telomerase, negative regulation of telomere maintenance via telomerase, positive regulation of telomere maintenance via telomerase.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-12-22.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-01-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-22 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-10 |

## Associated conditions {#conditions}

[tumor predisposition syndrome 3](https://sugi.bio/atlas/disease/tumor-predisposition-syndrome-3/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Tumor predisposition syndrome 3, Hereditary cancer-predisposing syndrome, not provided, Melanoma, cutaneous malignant, susceptibility to, 10, Glioma susceptibility 9, LONG TELOMERE SYNDROME, POT1-RELATED, POT1 Tumor Predisposition, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome.

## Same-residue context {#hotspot}

Residue **231** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [POT1 p.Arg231fs](/variant/pot1-p-arg231fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related POT1 variant pages (same residue, condition, or type): [POT1 p.Arg231Lys](/variant/pot1-p-arg231lys), [POT1 p.Arg231fs](/variant/pot1-p-arg231fs), [POT1 c.10-2A>C](/variant/pot1-c-10-minus-2a-c), [POT1 c.1163+1G>A](/variant/pot1-c-1163-plus-1g-a), [POT1 c.1164-1G>A](/variant/pot1-c-1164-minus-1g-a), [POT1 c.124+1G>C](/variant/pot1-c-124-plus-1g-c), [POT1 c.124+2T>C](/variant/pot1-c-124-plus-2t-c), [POT1 c.125-2A>G](/variant/pot1-c-125-minus-2a-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 950918). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*