Is TOP1 p.Ser394Phe (c.1181C>T) pathogenic?

TOP1 p.Ser394Phe (c.1181C>T) is classified Uncertain significance in TOP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-11). AlphaMissense: likely benign (0.1108); Very rare (popmax 0.00133%, afr).

How common is TOP1 p.Ser394Phe (c.1181C>T) in the general population?

TOP1 p.Ser394Phe (c.1181C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about TOP1 p.Ser394Phe (c.1181C>T)?

AlphaMissense predicts likely benign (score 0.1108) — an in-silico prediction, not a clinical call.

TOP1 p.Ser394Phe

c.1181C>T · VCV3328042

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1108 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.1108	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -9.18	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Pangolin	Δ0.33	gain · loss 0.12 · independent
Constraint at this position
Conservation	phyloP 6	GERP 2, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 1,032 bp · p 0.13 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

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

Grpmax group 0.00133% African / African-American · 1/74,938 alleles

Overall 6.2e-05% 1/1,613,960 alleles · very rare exomes 0/1,461,746 · genomes 1/152,214 · 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: TOP1
Protein: p.Ser394Phe
Coding: c.1181C>T
MANE Select: NM_003286
Type: single nucleotide variant
Location: chr20:41101226 (GRCh38)

Full TOP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/top1-p-ser394phe (accessed [today's date]).

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