Is GRN p.Ser6= (c.18C>T) pathogenic?

GRN p.Ser6= (c.18C>T) is classified Likely benign in GRN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-24). Ultra-rare (popmax 0.0329%, sas); Associated with GRN-related frontotemporal lobar degeneration with Tdp43 inclusions.

How common is GRN p.Ser6= (c.18C>T) in the general population?

GRN p.Ser6= (c.18C>T) is ultra-rare (popmax 0.0329%, sas) (gnomAD).

GRN p.Ser6=

Q: What condition is associated with GRN p.Ser6= (c.18C>T)?

GRN p.Ser6= (c.18C>T) is associated with GRN-related frontotemporal lobar degeneration with Tdp43 inclusions, neuronal ceroid lipofuscinosis 11 (ClinVar).

c.18C>T · rs768654819 · VCV2924078

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, sas)

Conditions

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions

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 4.1	GERP 0.12, phastCons 1
Overall
CADD	15.56	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0329% South Asian · 30/91,078 alleles

Filtering AF 0.0237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0205%

Overall 0.00211% 34/1,614,002 alleles · ultra-rare exomes 33/1,461,782 · genomes 1/152,220 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0329%	3,036
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.000254%	393,338

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.Ser6=
Coding: c.18C>T
MANE Select: NM_002087
dbSNP: rs768654819
Type: single nucleotide variant
Location: chr17:44349182 (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.Ser6Arg 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-ser6 (accessed [today's date]).

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