Is POT1 p.Pro446= (c.1338G>A) pathogenic?

POT1 p.Pro446= (c.1338G>A) is classified Benign/Likely benign in POT1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). Ultra-rare (popmax 0.0872%, eas); Associated with tumor predisposition syndrome 3.

What condition is associated with POT1 p.Pro446= (c.1338G>A)?

POT1 p.Pro446= (c.1338G>A) is associated with tumor predisposition syndrome 3, hereditary neoplastic syndrome, pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8 (ClinVar).

How common is POT1 p.Pro446= (c.1338G>A) in the general population?

POT1 p.Pro446= (c.1338G>A) is ultra-rare (popmax 0.0872%, eas) (gnomAD).

POT1 p.Pro446=

c.1338G>A · rs185651210 · VCV475037

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0872%, eas)

Conditions

tumor predisposition syndrome 3

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 0.12	GERP -3, phastCons 0.94
Overall
CADD	10.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0872% East Asian · 39/44,720 alleles

Filtering AF 0.0655% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.058%

Overall 0.00298% 48/1,609,710 alleles · ultra-rare exomes 38/1,457,750 · genomes 10/151,960 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0872%	1,147
Middle Eastern	0.0173%	5,776
African / African-American	0.00401%	24,961
Remaining individualsnot grpmax-eligible	0.00321%	31,172
European (non-Finnish)	0.000255%	392,326

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.Pro446=
Coding: c.1338G>A
MANE Select: NM_015450
dbSNP: rs185651210
Type: single nucleotide variant
Location: chr7:124841004 (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

tumor predisposition syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 8 cerebroretinal microangiopathy with calcifications and cysts 3

Similar variants

POT1 p.Pro446Leu Uncertain significance ★★ ⚠ same residue
POT1 p.Pro446Gln Conflicting classifications of pathogenicity ★ ⚠ 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-pro446 (accessed [today's date]).

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