Is GRN p.His96Arg (c.287A>G) pathogenic?

GRN p.His96Arg (c.287A>G) is classified Conflicting classifications of pathogenicity in GRN (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-04-28). AlphaMissense: likely benign (0.0576); Ultra-rare (popmax 0.036%, afr); Associated with Inborn genetic diseases.

How common is GRN p.His96Arg (c.287A>G) in the general population?

GRN p.His96Arg (c.287A>G) is ultra-rare (popmax 0.036%, afr) (gnomAD).

What do computational predictors say about GRN p.His96Arg (c.287A>G)?

AlphaMissense predicts likely benign (score 0.0576) — an in-silico prediction, not a clinical call.

GRN p.His96Arg

Q: What condition is associated with GRN p.His96Arg (c.287A>G)?

GRN p.His96Arg (c.287A>G) is associated with Inborn genetic diseases, GRN-related frontotemporal lobar degeneration with Tdp43 inclusions, neuronal ceroid lipofuscinosis 11 (ClinVar).

c.287A>G · rs139272628 · VCV587860

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0576 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.036%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0576	likely benign
REVEL	0.179	moderately benign-leaning
SaProt	LLR -5.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.6	GERP -2.4
Regional constraint	o/e 0.97	unconstrained · MANE · 2,212 bp · p 0.62 · regional, not allelic
Overall
CADD	0.076	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 0.036% African / African-American · 27/75,056 alleles

Filtering AF 0.0254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0218%

Overall 0.00539% 87/1,613,364 alleles · ultra-rare exomes 58/1,460,972 · genomes 29/152,392 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.036%	2,780
Admixed American	0.0183%	5,458
East Asian	0.00446%	22,443
European (non-Finnish)	0.00382%	26,208
Remaining individualsnot grpmax-eligible	0.0032%	31,248

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.His96Arg
Coding: c.287A>G
MANE Select: NM_002087
dbSNP: rs139272628
Type: single nucleotide variant
Location: chr17:44349689 (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

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 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
GRN c.934-1G>A Likely 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-his96arg (accessed [today's date]).

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