Is POT1 p.Val326= (c.978A>G) pathogenic?

POT1 p.Val326= (c.978A>G) is classified Likely benign in POT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-10). Very rare (popmax 0.00401%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with POT1 p.Val326= (c.978A>G)?

POT1 p.Val326= (c.978A>G) is associated with hereditary neoplastic syndrome, tumor predisposition syndrome 3 (ClinVar).

How common is POT1 p.Val326= (c.978A>G) in the general population?

POT1 p.Val326= (c.978A>G) is very rare (popmax 0.00401%, afr) (gnomAD).

POT1 p.Val326=

c.978A>G · rs143616208 · VCV765049

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.24	donor gain · deltas
Constraint at this position
Conservation	phyloP -0.1	GERP -3.9, phastCons 0.7
Overall
CADD	6.939	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,734 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000496%

Overall 0.000187% 3/1,605,772 alleles · very rare exomes 0/1,453,620 · genomes 3/152,152 · 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.Val326=
Coding: c.978A>G
MANE Select: NM_015450
dbSNP: rs143616208
Type: single nucleotide variant
Location: chr7:124846970 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 87.63 · 14 PDB

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.Val326Ile Uncertain significance ★★ ⚠ same residue
POT1 p.Val326Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
POT1 p.Val326Leu 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-val326 (accessed [today's date]).

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