Is TOP1 p.Pro195= (c.585G>A) pathogenic?

TOP1 p.Pro195= (c.585G>A) is classified Likely benign in TOP1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-07-25). Very rare (popmax 0.00703%, sas); Associated with TOP1-related disorder.

What condition is associated with TOP1 p.Pro195= (c.585G>A)?

TOP1 p.Pro195= (c.585G>A) is associated with TOP1-related disorder (ClinVar).

How common is TOP1 p.Pro195= (c.585G>A) in the general population?

TOP1 p.Pro195= (c.585G>A) is very rare (popmax 0.00703%, sas) (gnomAD).

TOP1 p.Pro195=

c.585G>A · rs368613261 · VCV3035753

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00703%, sas)

Conditions

TOP1-related disorder

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 1.2	GERP -3, phastCons 1
Overall
CADD	11.95	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00703% South Asian · 6/85,300 alleles

Filtering AF 0.00302% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.00185% 29/1,571,722 alleles · very rare exomes 25/1,419,596 · genomes 4/152,126 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00703%	14,217
African / African-American	0.00546%	18,312
East Asian	0.00229%	43,744
Admixed American	0.00185%	54,072
Finnishnot grpmax-eligible	0.00162%	61,870
European (non-Finnish)	0.00138%	72,315

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.Pro195=
Coding: c.585G>A
MANE Select: NM_003286
dbSNP: rs368613261
Type: single nucleotide variant
Location: chr20:41084539 (GRCh38)
Gene constraint: LOEUF 0.122 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.25 · 15 PDB
Residue 195: the 'disordered' region

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

Disease context

TOP1-related disorder

Similar variants

TOP1 p.Lys48= Benign ★★ same type
TOP1 p.Arg140Gln Uncertain significance ★ ⚠ same type
TOP1 p.Arg34Trp Uncertain significance ★ ⚠ same type
TOP1 p.Arg95Gln Uncertain significance ★ ⚠ same type
TOP1 p.Asn178His Uncertain significance ★ ⚠ same type
TOP1 p.Asn190Asp Uncertain significance ★ ⚠ same type
TOP1 p.Asn8Ser Uncertain significance ★ ⚠ same type
TOP1 p.Asp170Gly Uncertain significance ★ ⚠ same type

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-pro195 (accessed [today's date]).

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