Is GRN p.Pro166= (c.498G>A) pathogenic?

GRN p.Pro166= (c.498G>A) is classified Likely benign in GRN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-22). Very rare (popmax 0.00667%, amr); Associated with neuronal ceroid lipofuscinosis 11.

What condition is associated with GRN p.Pro166= (c.498G>A)?

GRN p.Pro166= (c.498G>A) is associated with neuronal ceroid lipofuscinosis 11, GRN-related frontotemporal lobar degeneration with Tdp43 inclusions (ClinVar).

How common is GRN p.Pro166= (c.498G>A) in the general population?

GRN p.Pro166= (c.498G>A) is very rare (popmax 0.00667%, amr) (gnomAD).

GRN p.Pro166=

c.498G>A · rs141873754 · VCV1616870

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

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 -1.4	GERP -2.8
Overall
CADD	6.363	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/59,984 alleles

Filtering AF 0.00367% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00329%

Overall 0.0039% 63/1,613,650 alleles · very rare exomes 61/1,461,620 · genomes 2/152,030 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,996
European (non-Finnish)	0.00466%	21,452
Remaining individualsnot grpmax-eligible	0.0032%	31,240
East Asian	0.00223%	44,886
African / African-American	0.00134%	74,840

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.Pro166=
Coding: c.498G>A
MANE Select: NM_002087
dbSNP: rs141873754
Type: single nucleotide variant
Location: chr17:44350477 (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 p.Pro166Leu Uncertain significance ★★ ⚠ same residue
GRN p.Pro166delinsLeuTer 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-pro166 (accessed [today's date]).

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