Is POT1 p.Asp219= (c.657C>T) pathogenic?

POT1 p.Asp219= (c.657C>T) is classified Likely benign in POT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-18). Very rare (popmax 0.0022%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with POT1 p.Asp219= (c.657C>T)?

POT1 p.Asp219= (c.657C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is POT1 p.Asp219= (c.657C>T) in the general population?

POT1 p.Asp219= (c.657C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

POT1 p.Asp219=

c.657C>T · VCV3308938

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

hereditary neoplastic syndrome

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 2.6	GERP -1.4, phastCons 1
Overall
CADD	3.91	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/90,858 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000248% 4/1,611,632 alleles · very rare exomes 4/1,459,408 · genomes 0/152,224 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,429
European (non-Finnish)	0.00017%	589,095

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.Asp219=
Coding: c.657C>T
MANE Select: NM_015450
Type: single nucleotide variant
Location: chr7:124859002 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 87.63 · 14 PDB
Residue 219: a β-strand

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.Asp219Glu Uncertain significance ★★ ⚠ same residue
POT1 p.Asp219Tyr Uncertain significance ★★ ⚠ same residue
POT1 p.Asp219Gly 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-asp219 (accessed [today's date]).

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