Is GRN p.Arg418Ter (c.1252C>T) pathogenic?

GRN p.Arg418Ter (c.1252C>T) is classified Pathogenic in GRN (ClinVar, Multiple submitters, 11 submitters; last evaluated 2025-02-14). Very rare (popmax 0.00133%, afr); Associated with GRN-related frontotemporal lobar degeneration with Tdp43 inclusions.

What condition is associated with GRN p.Arg418Ter (c.1252C>T)?

GRN p.Arg418Ter (c.1252C>T) is associated with GRN-related frontotemporal lobar degeneration with Tdp43 inclusions, amyotrophic lateral sclerosis type 10, neuronal ceroid lipofuscinosis 11 (ClinVar).

How common is GRN p.Arg418Ter (c.1252C>T) in the general population?

GRN p.Arg418Ter (c.1252C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

GRN p.Arg418Ter

c.1252C>T · rs63751180 · VCV98177

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

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	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 11 of 13
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.37	GERP -2.4
Overall
CADD	25.6	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 0.00133% African / African-American · 1/74,994 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000434% 7/1,613,786 alleles · very rare exomes 7/1,461,628 · genomes 0/152,158 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00157%	63,818
African / African-Americangrpmax	0.00133%	74,994
European (non-Finnish)	0.000424%	235,987

Finnish 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: GRN
Protein: p.Arg418Ter
Coding: c.1252C>T
MANE Select: NM_002087
dbSNP: rs63751180
Type: single nucleotide variant
Location: chr17:44352087 (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: amyotrophic lateral sclerosis type 10 neuronal ceroid lipofuscinosis 11

Similar variants

GRN p.Arg418Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
GRN p.Arg418Pro Uncertain significance ★ same residue
GRN c.1414-1G>T Pathogenic ★★ same condition
GRN c.1414-2A>G Pathogenic ★★ same condition
GRN c.264+1G>A Likely pathogenic ★★ same condition
GRN c.349+1G>C Pathogenic ★★ same condition
GRN c.599-1G>A Pathogenic/Likely pathogenic ★★ same condition
GRN c.709-1G>A 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-arg418ter (accessed [today's date]).

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