Is GRN p.Asp581Val (c.1742A>T) pathogenic?

GRN p.Asp581Val (c.1742A>T) is classified Conflicting classifications of pathogenicity in GRN (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-28). AlphaMissense: ambiguous (0.4975); Rare (popmax 0.143%, amr); Associated with GRN-related frontotemporal lobar degeneration with Tdp43 inclusions.

How common is GRN p.Asp581Val (c.1742A>T) in the general population?

GRN p.Asp581Val (c.1742A>T) is rare (popmax 0.143%, amr) (gnomAD).

What do computational predictors say about GRN p.Asp581Val (c.1742A>T)?

AlphaMissense predicts ambiguous (score 0.4975) — an in-silico prediction, not a clinical call.

GRN p.Asp581Val

Q: What condition is associated with GRN p.Asp581Val (c.1742A>T)?

GRN p.Asp581Val (c.1742A>T) is associated with GRN-related frontotemporal lobar degeneration with Tdp43 inclusions, neuronal ceroid lipofuscinosis 11 (ClinVar).

c.1742A>T · rs768223928 · VCV447473

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4975 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.143%, amr)

Conditions

GRN-related frontotemporal lobar degeneration with Tdp43 inclusions

Computational evidence

Protein change
AlphaMissense	0.4975	ambiguous
REVEL	0.52	indeterminate
SaProt	LLR -5.65	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 0.69, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 1,160 bp · p 0.13 · regional, not allelic
Overall
CADD	23.3	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 0.143% Admixed American · 86/60,008 alleles

Filtering AF 0.119% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.11%

Overall 0.0054% 87/1,611,674 alleles · rare exomes 77/1,459,524 · genomes 10/152,150 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.143%	698
Remaining individualsnot grpmax-eligible	0.0016%	62,470

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.Asp581Val
Coding: c.1742A>T
MANE Select: NM_002087
dbSNP: rs768223928
Type: single nucleotide variant
Location: chr17:44352758 (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.Asp581= Likely benign ★ same residue
GRN p.Asp581Asn 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

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-asp581val (accessed [today's date]).

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