Is POT1 p.Ala172Val (c.515C>T) pathogenic?

POT1 p.Ala172Val (c.515C>T) is classified Uncertain significance in POT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-28). AlphaMissense: ambiguous (0.5012); Very rare (popmax 8.48e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with POT1 p.Ala172Val (c.515C>T)?

POT1 p.Ala172Val (c.515C>T) is associated with hereditary neoplastic syndrome, tumor predisposition syndrome 3 (ClinVar).

How common is POT1 p.Ala172Val (c.515C>T) in the general population?

POT1 p.Ala172Val (c.515C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about POT1 p.Ala172Val (c.515C>T)?

AlphaMissense predicts ambiguous (score 0.5012) — an in-silico prediction, not a clinical call.

POT1 p.Ala172Val

c.515C>T · rs2485479537 · VCV1745712

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5012 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.5012	ambiguous
REVEL	0.193	benign-leaning
SaProt	LLR -8.75	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.7, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 44 kb · p 1.3e-06 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,788 alleles

Overall 6.2e-05% 1/1,613,620 alleles · very rare exomes 1/1,461,396 · genomes 0/152,224 · 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.Ala172Val
Coding: c.515C>T
MANE Select: NM_015450
dbSNP: rs2485479537
Type: single nucleotide variant
Location: chr7:124863381 (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.Ala172= Likely benign ★★ 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-ala172val (accessed [today's date]).

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