Is GRN p.Pro166Leu (c.497C>T) pathogenic?

GRN p.Pro166Leu (c.497C>T) is classified Uncertain significance in GRN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-02). AlphaMissense: likely benign (0.2392); Ultra-rare (popmax 0.0468%, eas); Associated with GRN-related frontotemporal lobar degeneration with Tdp43 inclusions.

How common is GRN p.Pro166Leu (c.497C>T) in the general population?

GRN p.Pro166Leu (c.497C>T) is ultra-rare (popmax 0.0468%, eas) (gnomAD).

What do computational predictors say about GRN p.Pro166Leu (c.497C>T)?

AlphaMissense predicts likely benign (score 0.2392) — an in-silico prediction, not a clinical call.

GRN p.Pro166Leu

Q: What condition is associated with GRN p.Pro166Leu (c.497C>T)?

GRN p.Pro166Leu (c.497C>T) is associated with GRN-related frontotemporal lobar degeneration with Tdp43 inclusions, neuronal ceroid lipofuscinosis 11 (ClinVar).

c.497C>T · rs368705304 · VCV323533

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2392 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0468%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions

Computational evidence

Protein change
AlphaMissense	0.2392	likely benign
REVEL	0.82	moderately pathogenic-leaning
SaProt	LLR -9.19	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 2,212 bp · p 0.62 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0468% East Asian · 21/44,890 alleles

Filtering AF 0.0313% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0263%

Overall 0.00403% 65/1,613,788 alleles · ultra-rare exomes 52/1,461,706 · genomes 13/152,082 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0468%	2,138
African / African-American	0.0294%	3,403
Admixed American	0.01%	9,999
South Asian	0.00768%	13,013
Remaining individualsnot grpmax-eligible	0.0064%	15,620
European (non-Finnish)	0.000424%	235,984

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.Pro166Leu
Coding: c.497C>T
MANE Select: NM_002087
dbSNP: rs368705304
Type: single nucleotide variant
Location: chr17:44350476 (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.Pro166= Likely benign ★★ 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-pro166leu (accessed [today's date]).

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