Is TOP1 p.Arg34Trp (c.100C>T) pathogenic?

TOP1 p.Arg34Trp (c.100C>T) is classified Uncertain significance in TOP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-07). AlphaMissense: ambiguous (0.417); Very rare (popmax 0.0011%, sas).

How common is TOP1 p.Arg34Trp (c.100C>T) in the general population?

TOP1 p.Arg34Trp (c.100C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about TOP1 p.Arg34Trp (c.100C>T)?

AlphaMissense predicts ambiguous (score 0.417) — an in-silico prediction, not a clinical call.

TOP1 p.Arg34Trp

c.100C>T · VCV3460094

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.417 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.417	ambiguous
REVEL	0.149	moderately benign-leaning
SaProt	LLR -13.04	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.2, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 55 kb · p 0.006 · regional, not allelic
Overall
CADD	28.3	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 0.0011% South Asian · 1/91,016 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,613,196 alleles · very rare exomes 6/1,461,168 · genomes 1/152,028 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,016
European (non-Finnish)	0.000509%	196,601

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.Arg34Trp
Coding: c.100C>T
MANE Select: NM_003286
Type: single nucleotide variant
Location: chr20:41061435 (GRCh38)
Gene constraint: LOEUF 0.122 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 80.25 · 15 PDB
Residue 34: the 'disordered' region

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

Similar variants

TOP1 p.Lys48= Benign ★★ same type
TOP1 p.Arg140Gln 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
TOP1 p.Lys161Arg 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-arg34trp (accessed [today's date]).

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