Is GRN p.Ser78fs (c.232dup) pathogenic?

GRN p.Ser78fs (c.232dup) is classified Pathogenic in GRN (ClinVar, Single submitter, 2 submitters; last evaluated 2017-02-01). Very rare (popmax 8.47e-05%, nfe); Associated with frontotemporal dementia.

What condition is associated with GRN p.Ser78fs (c.232dup)?

GRN p.Ser78fs (c.232dup) is associated with frontotemporal dementia (ClinVar).

How common is GRN p.Ser78fs (c.232dup) in the general population?

GRN p.Ser78fs (c.232dup) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

GRN p.Ser78fs

c.232dup · rs1567885658 · VCV599618

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

frontotemporal dementia

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 3 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.6	GERP -1.4, phastCons 0.064

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,052 alleles

Overall 6.19e-05% 1/1,614,224 alleles · very rare exomes 1/1,461,826 · genomes 0/152,398 · joint denominator

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.Ser78fs
Coding: c.232dup
MANE Select: NM_002087
dbSNP: rs1567885658
Type: Duplication
Location: chr17:44349518 (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

frontotemporal dementia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GRN p.Cys260fs Pathogenic ★★ same condition
GRN p.Cys30fs Pathogenic ★ same condition
GRN p.Cys416fs Pathogenic ★ same condition
GRN p.Ser129fs Pathogenic ★ same condition
GRN p.Cys253_Asp254delinsTer Pathogenic ★★ same condition
GRN p.Gln130fs Pathogenic ★★ same condition
GRN p.Asp254fs Pathogenic ★ same condition
GRN p.Cys482Ter 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-ser78fs (accessed [today's date]).

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