Is POT1 p.Pro592Leu (c.1775C>T) pathogenic?

POT1 p.Pro592Leu (c.1775C>T) is classified Uncertain significance in POT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-29). AlphaMissense: likely benign (0.2366); Very rare (popmax 0.00504%, amr); Associated with tumor predisposition syndrome 3.

What condition is associated with POT1 p.Pro592Leu (c.1775C>T)?

POT1 p.Pro592Leu (c.1775C>T) is associated with tumor predisposition syndrome 3, hereditary neoplastic syndrome (ClinVar).

How common is POT1 p.Pro592Leu (c.1775C>T) in the general population?

POT1 p.Pro592Leu (c.1775C>T) is very rare (popmax 0.00504%, amr) (gnomAD).

What do computational predictors say about POT1 p.Pro592Leu (c.1775C>T)?

AlphaMissense predicts likely benign (score 0.2366) — an in-silico prediction, not a clinical call.

POT1 p.Pro592Leu

c.1775C>T · rs1436064065 · VCV1430847

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2366 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00504%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

tumor predisposition syndrome 3

Computational evidence

Protein change
AlphaMissense	0.2366	likely benign
REVEL	0.488	indeterminate
SaProt	LLR -8.02	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 29 kb · p 0.48 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00504% Admixed American · 3/59,470 alleles

Filtering AF 0.00134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000671%

Overall 0.000187% 3/1,605,998 alleles · very rare exomes 3/1,454,084 · genomes 0/151,914 · 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.Pro592Leu
Coding: c.1775C>T
MANE Select: NM_015450
dbSNP: rs1436064065
Type: single nucleotide variant
Location: chr7:124825269 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 87.63 · 14 PDB

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.Pro592Ser Uncertain significance ★★ ⚠ same residue
POT1 p.Pro592Arg Uncertain significance ★ ⚠ same residue
POT1 p.Pro592Thr Uncertain significance ★ ⚠ 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

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-pro592leu (accessed [today's date]).

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