Is POT1 p.Lys433= (c.1299A>G) pathogenic?

POT1 p.Lys433= (c.1299A>G) is classified Conflicting classifications of pathogenicity in POT1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-05-22). Very rare (popmax 0.00133%, afr); Associated with tumor predisposition syndrome 3.

What condition is associated with POT1 p.Lys433= (c.1299A>G)?

POT1 p.Lys433= (c.1299A>G) is associated with tumor predisposition syndrome 3, hereditary neoplastic syndrome (ClinVar).

How common is POT1 p.Lys433= (c.1299A>G) in the general population?

POT1 p.Lys433= (c.1299A>G) is very rare (popmax 0.00133%, afr) (gnomAD).

POT1 p.Lys433=

c.1299A>G · rs1219744946 · VCV2194139

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

tumor predisposition syndrome 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.36	donor gain · deltas
Constraint at this position
Conservation	phyloP 2.7	GERP 0.49, phastCons 1
Overall
CADD	15.46	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,976 alleles

Overall 0.000124% 2/1,612,572 alleles · very rare exomes 2/1,460,446 · genomes 0/152,126 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,976
European (non-Finnish)	8.48e-05%	1,178,921

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.Lys433=
Coding: c.1299A>G
MANE Select: NM_015450
dbSNP: rs1219744946
Type: single nucleotide variant
Location: chr7:124841043 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 87.63 · 14 PDB
Residue 433: a β-strand

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

Also linked: hereditary neoplastic syndrome

Similar variants

POT1 p.Lys433Asn Uncertain significance ★★ ⚠ same residue
POT1 p.Lys433_Val434insTer 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
POT1 c.124+2T>C Likely pathogenic ★★ same condition
POT1 c.125-2A>G 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-lys433 (accessed [today's date]).

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