Is GRN p.Phe131= (c.393C>T) pathogenic?

GRN p.Phe131= (c.393C>T) is classified Likely benign in GRN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-01). Very rare (popmax 0.00223%, eas); Associated with GRN-related frontotemporal lobar degeneration with Tdp43 inclusions.

How common is GRN p.Phe131= (c.393C>T) in the general population?

GRN p.Phe131= (c.393C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

GRN p.Phe131=

Q: What condition is associated with GRN p.Phe131= (c.393C>T)?

GRN p.Phe131= (c.393C>T) is associated with GRN-related frontotemporal lobar degeneration with Tdp43 inclusions, neuronal ceroid lipofuscinosis 11 (ClinVar).

c.393C>T · rs149180605 · VCV323532

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

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.
REVEL	0.021	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -11	GERP -2.8
Overall
CADD	0.415	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,864 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000682% 11/1,613,912 alleles · very rare exomes 9/1,461,798 · genomes 2/152,114 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,250
East Asiangrpmax	0.00223%	44,864
South Asian	0.0022%	45,542
African / African-American	0.00133%	74,970
European (non-Finnish)	0.000424%	235,982

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe131=
Coding: c.393C>T
MANE Select: NM_002087
dbSNP: rs149180605
Type: single nucleotide variant
Location: chr17:44350271 (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.Phe131Leu 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-phe131 (accessed [today's date]).

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