Is POT1 p.Arg276= (c.828G>A) pathogenic?

POT1 p.Arg276= (c.828G>A) is classified Benign/Likely benign in POT1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-03). Rare (popmax 0.352%, afr); Associated with tumor predisposition syndrome 3.

What condition is associated with POT1 p.Arg276= (c.828G>A)?

POT1 p.Arg276= (c.828G>A) is associated with tumor predisposition syndrome 3, hereditary neoplastic syndrome (ClinVar).

How common is POT1 p.Arg276= (c.828G>A) in the general population?

POT1 p.Arg276= (c.828G>A) is rare (popmax 0.352%, afr) (gnomAD).

POT1 p.Arg276=

c.828G>A · rs76496261 · VCV475106

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.352%, afr)

Conditions

tumor predisposition syndrome 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.022	GERP -3.9, phastCons 0.94
Overall
CADD	5.849	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.352% African / African-American · 264/74,992 alleles

Filtering AF 0.317% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.304%

Overall 0.0197% 318/1,613,460 alleles · rare exomes 160/1,461,294 · genomes 158/152,166 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.352%	284
Remaining individualsnot grpmax-eligible	0.0416%	2,402
Admixed American	0.0383%	2,609
Middle Eastern	0.0165%	6,062
South Asian	0.0011%	91,026
European (non-Finnish)	0.000254%	393,187

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.Arg276=
Coding: c.828G>A
MANE Select: NM_015450
dbSNP: rs76496261
Type: single nucleotide variant
Location: chr7:124853013 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 87.63 · 14 PDB
Residue 276: 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.Arg276Ser Uncertain significance ★★ ⚠ same residue
POT1 p.Arg276Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
POT1 p.Arg276Lys 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-arg276 (accessed [today's date]).

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