Is TDP1 p.Ser299fs (c.896del) pathogenic?

TDP1 p.Ser299fs (c.896del) is classified Uncertain significance in TDP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-19). Very rare (popmax 0.000847%, nfe).

How common is TDP1 p.Ser299fs (c.896del) in the general population?

TDP1 p.Ser299fs (c.896del) is very rare (popmax 0.000847%, nfe) (gnomAD).

TDP1 p.Ser299fs

c.896del · rs773960264 · VCV631721

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 17
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000847% European (non-Finnish) · 10/1,180,036 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000682% 11/1,613,992 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,488
European (non-Finnish)grpmax	0.000847%	118,004

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: TDP1
Protein: p.Ser299fs
Coding: c.896del
MANE Select: NM_018319
dbSNP: rs773960264
Type: Deletion
Location: chr14:89984527 (GRCh38)
Gene constraint: LOEUF 0.983 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 81.20 · 48 PDB
Residue 299: an α-helix

Full TDP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TDP1 c.1131+1del Likely pathogenic ★ same type
TDP1 c.1731_1753+646del Likely pathogenic ★ same type
TDP1 p.Leu437_Tyr438insTer Uncertain significance ★ same type
TDP1 c.1131+184_1131+185del Benign ★ same type
TDP1 c.1317+118del Benign ★ 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/tdp1-p-ser299fs (accessed [today's date]).

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