Is GRN p.Ala89= (c.267C>T) pathogenic?

GRN p.Ala89= (c.267C>T) is classified Benign/Likely benign in GRN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-15). Rare (popmax 0.433%, sas); Associated with GRN-related frontotemporal lobar degeneration with Tdp43 inclusions.

How common is GRN p.Ala89= (c.267C>T) in the general population?

GRN p.Ala89= (c.267C>T) is rare (popmax 0.433%, sas) (gnomAD).

GRN p.Ala89=

Q: What condition is associated with GRN p.Ala89= (c.267C>T)?

GRN p.Ala89= (c.267C>T) is associated with GRN-related frontotemporal lobar degeneration with Tdp43 inclusions, neuronal ceroid lipofuscinosis 11 (ClinVar).

c.267C>T · rs201699327 · VCV1598641

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.433%, sas)

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 -6.4	GERP -2.4
Overall
CADD	1.281	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.433% South Asian · 394/91,070 alleles

Filtering AF 0.397% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.383%

Overall 0.0265% 428/1,612,530 alleles · rare exomes 406/1,460,162 · genomes 22/152,368 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.433%	231
Remaining individualsnot grpmax-eligible	0.032%	3,124
Middle Eastern	0.0165%	6,058
African / African-American	0.00533%	18,758
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,588
European (non-Finnish)	0.000679%	147,324

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.Ala89=
Coding: c.267C>T
MANE Select: NM_002087
dbSNP: rs201699327
Type: single nucleotide variant
Location: chr17:44349669 (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 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-ala89 (accessed [today's date]).

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