Is POT1 p.Ala172= (c.516A>C) pathogenic?

POT1 p.Ala172= (c.516A>C) is classified Likely benign in POT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-19). Very rare (popmax 0.0011%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with POT1 p.Ala172= (c.516A>C)?

POT1 p.Ala172= (c.516A>C) is associated with hereditary neoplastic syndrome, tumor predisposition syndrome 3 (ClinVar).

How common is POT1 p.Ala172= (c.516A>C) in the general population?

POT1 p.Ala172= (c.516A>C) is very rare (popmax 0.0011%, sas) (gnomAD).

POT1 p.Ala172=

c.516A>C · rs767849387 · VCV1745769

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, 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 -1.9	GERP -1
Overall
CADD	7.359	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/90,968 alleles

Overall 0.000124% 2/1,613,576 alleles · very rare exomes 1/1,461,392 · genomes 1/152,184 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,968
European (non-Finnish)	8.48e-05%	1,179,818

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.Ala172=
Coding: c.516A>C
MANE Select: NM_015450
dbSNP: rs767849387
Type: single nucleotide variant
Location: chr7:124863380 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 87.63 · 14 PDB
Residue 172: 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

Also linked: tumor predisposition syndrome 3

Similar variants

POT1 p.Ala172Val Uncertain significance ★★ ⚠ same residue
POT1 p.Ala172Gly Uncertain significance ★ ⚠ same residue
POT1 p.Ala172Thr 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-ala172 (accessed [today's date]).

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