Is POT1 p.Ser99Pro (c.295T>C) pathogenic?

POT1 p.Ser99Pro (c.295T>C) is classified Conflicting classifications of pathogenicity in POT1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-12-19). AlphaMissense: likely benign (0.0592); Very rare (popmax 0.00017%, nfe); Associated with tumor predisposition syndrome 3.

What condition is associated with POT1 p.Ser99Pro (c.295T>C)?

POT1 p.Ser99Pro (c.295T>C) is associated with tumor predisposition syndrome 3, hereditary neoplastic syndrome (ClinVar).

How common is POT1 p.Ser99Pro (c.295T>C) in the general population?

POT1 p.Ser99Pro (c.295T>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about POT1 p.Ser99Pro (c.295T>C)?

AlphaMissense predicts likely benign (score 0.0592) — an in-silico prediction, not a clinical call.

POT1 p.Ser99Pro

c.295T>C · rs2485481376 · VCV1798162

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0592 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tumor predisposition syndrome 3

Computational evidence

Protein change
AlphaMissense	0.0592	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -5.34	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 0.73	GERP -3.6, phastCons 0.98
Regional constraint	o/e 0.74	unconstrained · MANE · 44 kb · p 1.3e-06 · regional, not allelic
Overall
CADD	11.24	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,764 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,794 alleles · very rare exomes 2/1,461,504 · genomes 0/152,290 · 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.Ser99Pro
Coding: c.295T>C
MANE Select: NM_015450
dbSNP: rs2485481376
Type: single nucleotide variant
Location: chr7:124863601 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 87.63 · 14 PDB
Residue 99: 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.Ser99= Likely benign ★★ 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
POT1 c.1369+1G>A 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-ser99pro (accessed [today's date]).

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