Is POT1 p.Pro70Arg (c.209C>G) pathogenic?

POT1 p.Pro70Arg (c.209C>G) is classified Uncertain significance in POT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-29). AlphaMissense: likely pathogenic (0.9877); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with POT1 p.Pro70Arg (c.209C>G)?

POT1 p.Pro70Arg (c.209C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POT1 p.Pro70Arg (c.209C>G) in the general population?

POT1 p.Pro70Arg (c.209C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about POT1 p.Pro70Arg (c.209C>G)?

AlphaMissense predicts likely pathogenic (score 0.9877) — an in-silico prediction, not a clinical call.

POT1 p.Pro70Arg

c.209C>G · VCV4141925

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9877 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9877	likely pathogenic · top 1% in POT1
REVEL	0.746	pathogenic-leaning
SaProt	LLR -13.96	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 44 kb · p 1.3e-06 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: POT1
Protein: p.Pro70Arg
Coding: c.209C>G
MANE Select: NM_015450
Type: single nucleotide variant
Location: chr7:124870957 (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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

POT1 p.Pro70Ser Uncertain significance ★★ ⚠ same residue
POT1 p.Pro70= Likely benign ★ same residue
POT1 p.Pro70Ala 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-pro70arg (accessed [today's date]).

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