Is POT1 p.Val519Phe (c.1555G>T) pathogenic?

POT1 p.Val519Phe (c.1555G>T) is classified Uncertain significance in POT1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-31). AlphaMissense: likely benign (0.0985); Very rare (popmax 0.00134%, afr); Associated with tumor predisposition syndrome 3.

What condition is associated with POT1 p.Val519Phe (c.1555G>T)?

POT1 p.Val519Phe (c.1555G>T) is associated with tumor predisposition syndrome 3, hereditary neoplastic syndrome (ClinVar).

How common is POT1 p.Val519Phe (c.1555G>T) in the general population?

POT1 p.Val519Phe (c.1555G>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about POT1 p.Val519Phe (c.1555G>T)?

AlphaMissense predicts likely benign (score 0.0985) — an in-silico prediction, not a clinical call.

POT1 p.Val519Phe

c.1555G>T · rs776873207 · VCV651671

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0985 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tumor predisposition syndrome 3

Computational evidence

Protein change
AlphaMissense	0.0985	likely benign
REVEL	0.121	moderately benign-leaning
SaProt	LLR -8.31	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.064	GERP -0.74
Regional constraint	o/e 0.96	unconstrained · MANE · 29 kb · p 0.48 · regional, not allelic
Overall
CADD	11.71	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 0.00134% African / African-American · 1/74,828 alleles

Overall 6.23e-05% 1/1,606,226 alleles · very rare exomes 1/1,454,022 · genomes 0/152,204 · 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.Val519Phe
Coding: c.1555G>T
MANE Select: NM_015450
dbSNP: rs776873207
Type: single nucleotide variant
Location: chr7:124829293 (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.Val519= Likely benign ★★ same residue
POT1 p.Val519Ile Conflicting classifications of pathogenicity ★ ⚠ 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-val519phe (accessed [today's date]).

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