Is POT1 p.Phe375Ser (c.1124T>C) pathogenic?

POT1 p.Phe375Ser (c.1124T>C) is classified Conflicting classifications of pathogenicity in POT1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-03-30). AlphaMissense: likely benign (0.1462); Very rare (popmax 0.00224%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with POT1 p.Phe375Ser (c.1124T>C)?

POT1 p.Phe375Ser (c.1124T>C) is associated with hereditary neoplastic syndrome, tumor predisposition syndrome 3 (ClinVar).

How common is POT1 p.Phe375Ser (c.1124T>C) in the general population?

POT1 p.Phe375Ser (c.1124T>C) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about POT1 p.Phe375Ser (c.1124T>C)?

AlphaMissense predicts likely benign (score 0.1462) — an in-silico prediction, not a clinical call.

POT1 p.Phe375Ser

c.1124T>C · rs2485401809 · VCV1798744

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1462 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1462	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -4.20	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.37	GERP 0.43, phastCons 0.12
Regional constraint	o/e 0.96	unconstrained · MANE · 29 kb · p 0.48 · regional, not allelic
Overall
CADD	16.53	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 0.00224% East Asian · 1/44,732 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00025% 4/1,603,166 alleles · very rare exomes 4/1,450,918 · genomes 0/152,248 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,732
European (non-Finnish)	0.000255%	392,494

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.Phe375Ser
Coding: c.1124T>C
MANE Select: NM_015450
dbSNP: rs2485401809
Type: single nucleotide variant
Location: chr7:124842846 (GRCh38)
Gene constraint: LOEUF 0.871 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 87.63 · 14 PDB
Residue 375: an α-helix

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.Phe375Ile Uncertain significance ★★ ⚠ same residue
POT1 p.Phe375fs Pathogenic ★ 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-phe375ser (accessed [today's date]).

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