Is POT1 p.Ser103= (c.309T>A) pathogenic?

POT1 p.Ser103= (c.309T>A) is classified Likely benign in POT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-09). Very rare (popmax 0.00153%, nfe); Associated with tumor predisposition syndrome 3.

What condition is associated with POT1 p.Ser103= (c.309T>A)?

POT1 p.Ser103= (c.309T>A) is associated with tumor predisposition syndrome 3, hereditary neoplastic syndrome (ClinVar).

How common is POT1 p.Ser103= (c.309T>A) in the general population?

POT1 p.Ser103= (c.309T>A) is very rare (popmax 0.00153%, nfe) (gnomAD).

POT1 p.Ser103=

c.309T>A · rs2485481287 · VCV2856983

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Conditions

tumor predisposition syndrome 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP -1, phastCons 1
Overall
CADD	7.438	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00153% European (non-Finnish) · 18/1,179,824 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00112% 18/1,613,894 alleles · very rare exomes 18/1,461,618 · genomes 0/152,276 · 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.Ser103=
Coding: c.309T>A
MANE Select: NM_015450
dbSNP: rs2485481287
Type: single nucleotide variant
Location: chr7:124863587 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 87.63 · 14 PDB
Residue 103: 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.Ser103Cys Uncertain significance ★ ⚠ same residue
POT1 p.Ser103Phe 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
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-ser103 (accessed [today's date]).

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