Is TOP1 p.Arg349= (c.1047G>A) pathogenic?

TOP1 p.Arg349= (c.1047G>A) is classified Benign in TOP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-10-17). Low-frequency (popmax 2.8%, afr).

How common is TOP1 p.Arg349= (c.1047G>A) in the general population?

TOP1 p.Arg349= (c.1047G>A) is low-frequency (popmax 2.8%, afr) (gnomAD).

TOP1 p.Arg349=

c.1047G>A · rs6029545 · VCV783862

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.8%, afr)

⚠ 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
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 1.9	GERP -0.1, phastCons 1
Overall
CADD	7.804	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.8% African / African-American · 2,100/75,002 alleles

Filtering AF 2.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.66%

Overall 0.145% 2,346/1,613,886 alleles · low-frequency exomes 1,162/1,461,620 · genomes 1,184/152,266 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.8%	36
Admixed American	0.163%	613
Remaining individualsnot grpmax-eligible	0.163%	613
Middle Eastern	0.099%	1,010
South Asian	0.00769%	13,010
European (non-Finnish)	0.0028%	35,752

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.Arg349=
Coding: c.1047G>A
MANE Select: NM_003286
dbSNP: rs6029545
Type: single nucleotide variant
Location: chr20:41100127 (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-arg349 (accessed [today's date]).

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