Is GRN p.Asp33= (c.99C>T) pathogenic?

GRN p.Asp33= (c.99C>T) is classified Benign/Likely benign in GRN (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-06-01). Rare (popmax 0.445%, nfe); Associated with GRN-related frontotemporal lobar degeneration with Tdp43 inclusions.

How common is GRN p.Asp33= (c.99C>T) in the general population?

GRN p.Asp33= (c.99C>T) is rare (popmax 0.445%, nfe) (gnomAD).

GRN p.Asp33=

Q: What condition is associated with GRN p.Asp33= (c.99C>T)?

GRN p.Asp33= (c.99C>T) is associated with GRN-related frontotemporal lobar degeneration with Tdp43 inclusions, neuronal ceroid lipofuscinosis 11 (ClinVar).

c.99C>T · rs63750742 · VCV98123

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

rare (popmax 0.445%, nfe)

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.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.14	GERP -1, phastCons 0.005
Overall
CADD	7.418	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.445% European (non-Finnish) · 5,246/1,180,008 alleles

Filtering AF 0.434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.43%

Overall 0.357% 5,767/1,613,960 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.445%	225
Remaining individualsnot grpmax-eligible	0.336%	298
Admixed American	0.143%	698
Finnishnot grpmax-eligible	0.13%	769
Middle Eastern	0.0825%	1,212
South Asian	0.0812%	1,231
African / African-American	0.0799%	1,251
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,803
East Asian	0.00223%	44,890

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.Asp33=
Coding: c.99C>T
MANE Select: NM_002087
dbSNP: rs63750742
Type: single nucleotide variant
Location: chr17:44349263 (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.Asp33Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
GRN p.Asp33fs Pathogenic 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-asp33 (accessed [today's date]).

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