Is POT1 p.Arg231Ser (c.693A>T) pathogenic?

POT1 p.Arg231Ser (c.693A>T) is classified Uncertain significance in POT1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-22). AlphaMissense: likely benign (0.2284); Very rare (popmax 8.51e-05%, nfe); Associated with tumor predisposition syndrome 3.

What condition is associated with POT1 p.Arg231Ser (c.693A>T)?

POT1 p.Arg231Ser (c.693A>T) is associated with tumor predisposition syndrome 3, hereditary neoplastic syndrome (ClinVar).

How common is POT1 p.Arg231Ser (c.693A>T) in the general population?

POT1 p.Arg231Ser (c.693A>T) is very rare (popmax 8.51e-05%, nfe) (gnomAD).

What do computational predictors say about POT1 p.Arg231Ser (c.693A>T)?

AlphaMissense predicts likely benign (score 0.2284) — an in-silico prediction, not a clinical call.

POT1 p.Arg231Ser

c.693A>T · rs1795514618 · VCV950918

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2284 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.51e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tumor predisposition syndrome 3

Computational evidence

Protein change
AlphaMissense	0.2284	likely benign
REVEL	0.021	moderately benign-leaning
SaProt	LLR -7.86	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.20	donor loss, 9 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.45	GERP -3.7, phastCons 0.98
Regional constraint	o/e 0.74	unconstrained · MANE · 44 kb · p 1.3e-06 · regional, not allelic
Overall
CADD	19.65	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 8.51e-05% European (non-Finnish) · 1/1,174,402 alleles

Overall 6.23e-05% 1/1,605,018 alleles · very rare exomes 1/1,452,774 · genomes 0/152,244 · 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.Arg231Ser
Coding: c.693A>T
MANE Select: NM_015450
dbSNP: rs1795514618
Type: single nucleotide variant
Location: chr7:124858966 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 87.63 · 14 PDB
Residue 231: an α-helix

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.Arg231Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
POT1 p.Arg231fs Pathogenic ★ 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-arg231ser (accessed [today's date]).

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