Is GRN p.Ala577Ser (c.1729G>T) pathogenic?

GRN p.Ala577Ser (c.1729G>T) is classified Uncertain significance in GRN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-10). AlphaMissense: likely benign (0.07); Very rare (popmax 0.00446%, eas); Associated with Inborn genetic diseases.

What condition is associated with GRN p.Ala577Ser (c.1729G>T)?

GRN p.Ala577Ser (c.1729G>T) is associated with Inborn genetic diseases (ClinVar).

How common is GRN p.Ala577Ser (c.1729G>T) in the general population?

GRN p.Ala577Ser (c.1729G>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about GRN p.Ala577Ser (c.1729G>T)?

AlphaMissense predicts likely benign (score 0.07) — an in-silico prediction, not a clinical call.

GRN p.Ala577Ser

c.1729G>T · rs1449276120 · VCV2475395

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.07 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.07	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -6.60	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 0.32	GERP -2.8
Regional constraint	o/e 0.92	unconstrained · MANE · 1,160 bp · p 0.13 · regional, not allelic
Overall
CADD	0.596	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,882 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000137% 2/1,459,288 alleles · very rare

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.Ala577Ser
Coding: c.1729G>T
MANE Select: NM_002087
dbSNP: rs1449276120
Type: single nucleotide variant
Location: chr17:44352745 (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

Similar variants

GRN p.Ala577Val Uncertain significance ★ ⚠ same residue
GRN p.Ala577= Likely benign ★ same residue
GRN p.Ala276Val Uncertain significance ★★ ⚠ same condition
GRN p.Ala566Thr Uncertain significance ★★ ⚠ same condition
GRN p.Arg212Gln Uncertain significance ★★ ⚠ same condition
GRN p.Arg212Trp Uncertain significance ★★ ⚠ same condition
GRN p.Arg298Cys Uncertain significance ★★ ⚠ same condition
GRN p.Arg432Cys Uncertain significance ★★ ⚠ 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-ala577ser (accessed [today's date]).

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