Is GRN p.Pro587fs (c.1760del) pathogenic?

GRN p.Pro587fs (c.1760del) is classified Uncertain significance in GRN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-10). Very rare (popmax 0.00329%, sas); Associated with GRN-related frontotemporal lobar degeneration with Tdp43 inclusions.

How common is GRN p.Pro587fs (c.1760del) in the general population?

GRN p.Pro587fs (c.1760del) is very rare (popmax 0.00329%, sas) (gnomAD).

GRN p.Pro587fs

Q: What condition is associated with GRN p.Pro587fs (c.1760del)?

GRN p.Pro587fs (c.1760del) is associated with GRN-related frontotemporal lobar degeneration with Tdp43 inclusions, neuronal ceroid lipofuscinosis 11 (ClinVar).

c.1760del · rs769106670 · VCV3067343

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Conditions

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (13 of 13) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.22	GERP -3.3
Overall
CADD	21.8	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 0.00329% South Asian · 3/91,096 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000745% 12/1,611,764 alleles · very rare exomes 9/1,459,610 · genomes 3/152,154 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,365
European (non-Finnish)	0.000763%	131,107

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: GRN
Protein: p.Pro587fs
Coding: c.1760del
MANE Select: NM_002087
dbSNP: rs769106670
Type: Deletion
Location: chr17:44352774 (GRCh38)
Gene constraint: LOEUF 0.59 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 76.74 · 8 PDB

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

Disease context

Also linked: neuronal ceroid lipofuscinosis 11

Similar variants

GRN p.Pro587Ser Uncertain significance ★★ ⚠ same residue
GRN p.Pro587= Likely benign ★ same residue
GRN p.Arg198fs Pathogenic ★★ same condition
GRN p.Asp128fs Pathogenic/Likely pathogenic ★★ same condition
GRN p.Cys157fs Pathogenic ★★ same condition
GRN p.Gln130fs Pathogenic ★★ same condition
GRN p.Gln337fs Pathogenic/Likely pathogenic ★★ same condition
GRN p.Gly35fs Pathogenic ★★ same condition

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/grn-p-pro587fs (accessed [today's date]).

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