Is POT1 p.Arg273= (c.819G>A) pathogenic?

POT1 p.Arg273= (c.819G>A) is classified Uncertain significance in POT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-28). Very rare (popmax 8.48e-05%, nfe); Associated with tumor predisposition syndrome 3.

What condition is associated with POT1 p.Arg273= (c.819G>A)?

POT1 p.Arg273= (c.819G>A) is associated with tumor predisposition syndrome 3 (ClinVar).

How common is POT1 p.Arg273= (c.819G>A) in the general population?

POT1 p.Arg273= (c.819G>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

POT1 p.Arg273=

c.819G>A · rs1233171904 · VCV2744690

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

tumor predisposition syndrome 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.11	GERP -1.3, phastCons 0.53
Overall
CADD	7.58	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,520 alleles

Overall 6.2e-05% 1/1,613,292 alleles · very rare exomes 0/1,461,270 · genomes 1/152,022 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: POT1
Protein: p.Arg273=
Coding: c.819G>A
MANE Select: NM_015450
dbSNP: rs1233171904
Type: single nucleotide variant
Location: chr7:124853022 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 87.63 · 14 PDB
Residue 273: a UniProt-annotated variant site (in tpds3; complete abolition of pot1-dna complex formation, thus disrupting the interaction with telomeres and leading to elongated telomeres); a UniProt-annotated variant site (in tpds3; likely pathogenic; decreased dna binding); the 'dna-binding' region

Full POT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

tumor predisposition syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

POT1 p.Arg273Trp Uncertain significance ★★ ⚠ same residue
POT1 p.Arg273Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
POT1 p.Arg273Gly Uncertain significance ★ ⚠ same residue
POT1 p.Arg273Leu Pathogenic same residue
POT1 c.10-2A>C Pathogenic/Likely pathogenic ★★ same condition
POT1 c.1163+1G>A Likely pathogenic ★★ same condition
POT1 c.1164-1G>A Pathogenic/Likely pathogenic ★★ same condition
POT1 c.124+1G>C Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pot1-p-arg273 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown