Is GRN p.Ser449Arg (c.1347C>G) pathogenic?

GRN p.Ser449Arg (c.1347C>G) is classified Uncertain significance in GRN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-24). AlphaMissense: ambiguous (0.3719); Very rare (popmax 0.00223%, eas); Associated with neuronal ceroid lipofuscinosis 11.

What condition is associated with GRN p.Ser449Arg (c.1347C>G)?

GRN p.Ser449Arg (c.1347C>G) is associated with neuronal ceroid lipofuscinosis 11, GRN-related frontotemporal lobar degeneration with Tdp43 inclusions (ClinVar).

How common is GRN p.Ser449Arg (c.1347C>G) in the general population?

GRN p.Ser449Arg (c.1347C>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about GRN p.Ser449Arg (c.1347C>G)?

AlphaMissense predicts ambiguous (score 0.3719) — an in-silico prediction, not a clinical call.

GRN p.Ser449Arg

c.1347C>G · rs1033064351 · VCV2162242

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3719 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

neuronal ceroid lipofuscinosis 11

Computational evidence

Protein change
AlphaMissense	0.3719	ambiguous
REVEL	0.165	moderately benign-leaning
SaProt	LLR -7.77	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.96	donor gain · deltas
Pangolin	Δ0.69	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 1.2	GERP 0.33, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 1,160 bp · p 0.13 · regional, not allelic
Overall
CADD	25.6	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 0.00223% East Asian · 1/44,882 alleles

Overall 0.000124% 2/1,613,534 alleles · very rare exomes 2/1,461,204 · genomes 0/152,330 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,882
Remaining individualsnot grpmax-eligible	0.0016%	62,504

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.Ser449Arg
Coding: c.1347C>G
MANE Select: NM_002087
dbSNP: rs1033064351
Type: single nucleotide variant
Location: chr17:44352182 (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 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-ser449arg (accessed [today's date]).

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