Is GRN p.Pro458Arg (c.1373C>G) pathogenic?

GRN p.Pro458Arg (c.1373C>G) is classified Uncertain significance in GRN (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-02). AlphaMissense: likely benign (0.0859); Absent from gnomAD v4.1; Associated with GRN-related frontotemporal lobar degeneration with Tdp43 inclusions.

How common is GRN p.Pro458Arg (c.1373C>G) in the general population?

GRN p.Pro458Arg (c.1373C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GRN p.Pro458Arg (c.1373C>G)?

AlphaMissense predicts likely benign (score 0.0859) — an in-silico prediction, not a clinical call.

GRN p.Pro458Arg

Q: What condition is associated with GRN p.Pro458Arg (c.1373C>G)?

GRN p.Pro458Arg (c.1373C>G) is associated with GRN-related frontotemporal lobar degeneration with Tdp43 inclusions, neuronal ceroid lipofuscinosis 11 (ClinVar).

c.1373C>G · rs63750537 · VCV1474441

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0859 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions

Computational evidence

Protein change
AlphaMissense	0.0859	likely benign
REVEL	0.324	indeterminate
SaProt	LLR -3.83	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 0.35, phastCons 0.53
Regional constraint	o/e 0.92	unconstrained · MANE · 1,160 bp · p 0.13 · regional, not allelic
Overall
CADD	17.31	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GRN
Protein: p.Pro458Arg
Coding: c.1373C>G
MANE Select: NM_002087
dbSNP: rs63750537
Type: single nucleotide variant
Location: chr17:44352208 (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.Pro458Leu Uncertain significance ★★ ⚠ same residue
GRN p.Pro458= Likely benign ★ 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-pro458arg (accessed [today's date]).

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