Is GRN p.Asp128= (c.384T>C) pathogenic?

GRN p.Asp128= (c.384T>C) is classified Benign/Likely benign in GRN (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-02-02). Common (popmax 27%, eas) — too common for a highly-penetrant pathogenic allele; Associated with GRN-related frontotemporal lobar degeneration with Tdp43 inclusions.

GRN p.Asp128=

Q: What condition is associated with GRN p.Asp128= (c.384T>C)?

GRN p.Asp128= (c.384T>C) is associated with GRN-related frontotemporal lobar degeneration with Tdp43 inclusions, neuronal ceroid lipofuscinosis 11 (ClinVar).

Q: How common is GRN p.Asp128= (c.384T>C) in the general population?

GRN p.Asp128= (c.384T>C) is common (popmax 27%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.384T>C · rs25646 · VCV98137

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

gnomAD v4.1

Common

common (popmax 27%, eas) — too common for a highly-penetrant pathogenic allele

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.
REVEL	0.003	strongly benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -4	GERP -2.8
Overall
CADD	0.454	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 27% East Asian · 12,120/44,854 alleles

Filtering AF 26.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 26.5%

Overall 3.59% 57,976/1,613,744 alleles · common exomes 53,149/1,461,590 · genomes 4,827/152,154 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	27%	4
South Asian	7.68%	13
Ashkenazi Jewishnot grpmax-eligible	6.49%	15
Admixed American	5.29%	19
Remaining individualsnot grpmax-eligible	4.25%	24
Middle Eastern	4.01%	25
European (non-Finnish)	2.54%	39
Finnishnot grpmax-eligible	0.634%	158
African / African-American	0.605%	165

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.Asp128=
Coding: c.384T>C
MANE Select: NM_002087
dbSNP: rs25646
Type: single nucleotide variant
Location: chr17:44350262 (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.Asp128fs Pathogenic/Likely pathogenic ★★ same residue
GRN p.Asp128His 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-asp128 (accessed [today's date]).

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