Is GRN p.Pro504Leu (c.1511C>T) pathogenic?

GRN p.Pro504Leu (c.1511C>T) is classified Uncertain significance in GRN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-20). AlphaMissense: likely benign (0.0881); Very rare (popmax 0.000254%, nfe); Associated with neuronal ceroid lipofuscinosis 11.

What condition is associated with GRN p.Pro504Leu (c.1511C>T)?

GRN p.Pro504Leu (c.1511C>T) is associated with neuronal ceroid lipofuscinosis 11, GRN-related frontotemporal lobar degeneration with Tdp43 inclusions (ClinVar).

How common is GRN p.Pro504Leu (c.1511C>T) in the general population?

GRN p.Pro504Leu (c.1511C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about GRN p.Pro504Leu (c.1511C>T)?

AlphaMissense predicts likely benign (score 0.0881) — an in-silico prediction, not a clinical call.

GRN p.Pro504Leu

c.1511C>T · rs1339672875 · VCV1967834

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0881 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis 11

Computational evidence

Protein change
AlphaMissense	0.0881	likely benign
REVEL	0.09	moderately benign-leaning
SaProt	LLR -6.66	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.24	GERP 0.31
Regional constraint	o/e 0.92	unconstrained · MANE · 1,160 bp · p 0.13 · regional, not allelic
Overall
CADD	6.822	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,002 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,128 alleles · very rare exomes 3/1,461,762 · genomes 0/152,366 · joint denominator

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.Pro504Leu
Coding: c.1511C>T
MANE Select: NM_002087
dbSNP: rs1339672875
Type: single nucleotide variant
Location: chr17:44352438 (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.Pro504Ala 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
GRN c.709-2A>G 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-pro504leu (accessed [today's date]).

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