Is POT1 p.Asp129Val (c.386A>T) pathogenic?

POT1 p.Asp129Val (c.386A>T) is classified Uncertain significance in POT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-13). AlphaMissense: likely pathogenic (0.8223); Absent from gnomAD v4.1; Associated with tumor predisposition syndrome 3.

What condition is associated with POT1 p.Asp129Val (c.386A>T)?

POT1 p.Asp129Val (c.386A>T) is associated with tumor predisposition syndrome 3 (ClinVar).

How common is POT1 p.Asp129Val (c.386A>T) in the general population?

POT1 p.Asp129Val (c.386A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about POT1 p.Asp129Val (c.386A>T)?

AlphaMissense predicts likely pathogenic (score 0.8223) — an in-silico prediction, not a clinical call.

POT1 p.Asp129Val

c.386A>T · rs2116542079 · VCV2709216

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8223 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

tumor predisposition syndrome 3

Computational evidence

Protein change
AlphaMissense	0.8223	likely pathogenic
REVEL	0.567	indeterminate
SaProt	LLR -14.94	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 44 kb · p 1.3e-06 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: POT1
Protein: p.Asp129Val
Coding: c.386A>T
MANE Select: NM_015450
dbSNP: rs2116542079
Type: single nucleotide variant
Location: chr7:124863510 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 87.63 · 14 PDB
Residue 129: 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

Similar variants

POT1 p.Asp129Asn Uncertain significance ★★ ⚠ same residue
POT1 p.Asp129Gly 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
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-asp129val (accessed [today's date]).

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