Is POT1 p.Val183= (c.549A>G) pathogenic?

POT1 p.Val183= (c.549A>G) is classified Likely benign in POT1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-08). Very rare (popmax 0.00347%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with POT1 p.Val183= (c.549A>G)?

POT1 p.Val183= (c.549A>G) is associated with hereditary neoplastic syndrome, tumor predisposition syndrome 3 (ClinVar).

How common is POT1 p.Val183= (c.549A>G) in the general population?

POT1 p.Val183= (c.549A>G) is very rare (popmax 0.00347%, amr) (gnomAD).

POT1 p.Val183=

c.549A>G · rs758095637 · VCV1160473

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00347%, amr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.9	GERP -3.9
Overall
CADD	0.619	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00347% Admixed American · 2/57,704 alleles

Filtering AF 0.000575% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000215%

Overall 0.000253% 4/1,583,866 alleles · very rare exomes 3/1,431,708 · genomes 1/152,158 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00347%	28,852
European (non-Finnish)	0.000172%	581,879

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.Val183=
Coding: c.549A>G
MANE Select: NM_015450
dbSNP: rs758095637
Type: single nucleotide variant
Location: chr7:124859110 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 87.63 · 14 PDB
Residue 183: 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.Val183Ile Uncertain significance ★★ ⚠ same residue
POT1 p.Val183Ala Uncertain significance ★ ⚠ same residue
POT1 p.Val183Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
POT1 p.Val183Leu 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

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-val183 (accessed [today's date]).

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