Is GRN p.Thr409= (c.1227G>T) pathogenic?

GRN p.Thr409= (c.1227G>T) is classified Likely benign in GRN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-03). Ultra-rare (popmax 0.0147%, afr); Associated with Inborn genetic diseases.

How common is GRN p.Thr409= (c.1227G>T) in the general population?

GRN p.Thr409= (c.1227G>T) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

GRN p.Thr409=

Q: What condition is associated with GRN p.Thr409= (c.1227G>T)?

GRN p.Thr409= (c.1227G>T) is associated with Inborn genetic diseases, GRN-related frontotemporal lobar degeneration with Tdp43 inclusions, neuronal ceroid lipofuscinosis 11 (ClinVar).

c.1227G>T · rs140298583 · VCV1754633

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Conditions

Inborn genetic diseases

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 -6.2	GERP -2.8
Overall
CADD	0.056	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0147% African / African-American · 11/74,800 alleles

Filtering AF 0.00817% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00634%

Overall 0.000682% 11/1,612,938 alleles · ultra-rare exomes 0/1,461,272 · genomes 11/151,666 · 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.Thr409=
Coding: c.1227G>T
MANE Select: NM_002087
dbSNP: rs140298583
Type: single nucleotide variant
Location: chr17:44352062 (GRCh38)
Gene constraint: LOEUF 0.59 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 76.74 · 8 PDB
Residue 409: a β-strand

Full GRN gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: GRN-related frontotemporal lobar degeneration with Tdp43 inclusions neuronal ceroid lipofuscinosis 11

Similar variants

GRN p.Thr409Met 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-thr409 (accessed [today's date]).

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