Is GRN p.Asp518= (c.1554C>T) pathogenic?

GRN p.Asp518= (c.1554C>T) is classified Likely benign in GRN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-18). Very rare (popmax 0.00195%, nfe); Associated with neuronal ceroid lipofuscinosis 11.

What condition is associated with GRN p.Asp518= (c.1554C>T)?

GRN p.Asp518= (c.1554C>T) is associated with neuronal ceroid lipofuscinosis 11, GRN-related frontotemporal lobar degeneration with Tdp43 inclusions (ClinVar).

How common is GRN p.Asp518= (c.1554C>T) in the general population?

GRN p.Asp518= (c.1554C>T) is very rare (popmax 0.00195%, nfe) (gnomAD).

GRN p.Asp518=

c.1554C>T · rs189075184 · VCV2200465

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Conditions

neuronal ceroid lipofuscinosis 11

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -14	GERP -3.1
Overall
CADD	0.378	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00195% European (non-Finnish) · 23/1,179,954 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00155% 25/1,614,072 alleles · very rare exomes 22/1,461,746 · genomes 3/152,326 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00195%	51,302
African / African-American	0.00133%	75,064
South Asian	0.0011%	91,092

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.Asp518=
Coding: c.1554C>T
MANE Select: NM_002087
dbSNP: rs189075184
Type: single nucleotide variant
Location: chr17:44352481 (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

neuronal ceroid lipofuscinosis 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: GRN-related frontotemporal lobar degeneration with Tdp43 inclusions

For CLN11 disease (Orphanet):

Onset: Adolescent, Infancy

Similar variants

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
GRN c.709-2A>G Pathogenic ★★ same condition
GRN c.934-1G>A Likely 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-asp518 (accessed [today's date]).

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