Is GRN p.Pro275Ser (c.823C>T) pathogenic?

GRN p.Pro275Ser (c.823C>T) is classified Uncertain significance in GRN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-04). AlphaMissense: likely benign (0.1035); Very rare (popmax 6.2e-05%); Associated with Inborn genetic diseases.

What condition is associated with GRN p.Pro275Ser (c.823C>T)?

GRN p.Pro275Ser (c.823C>T) is associated with Inborn genetic diseases (ClinVar).

How common is GRN p.Pro275Ser (c.823C>T) in the general population?

GRN p.Pro275Ser (c.823C>T) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about GRN p.Pro275Ser (c.823C>T)?

AlphaMissense predicts likely benign (score 0.1035) — an in-silico prediction, not a clinical call.

GRN p.Pro275Ser

c.823C>T · rs2510056489 · VCV2491036

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1035 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1035	likely benign
REVEL	0.367	indeterminate
SaProt	LLR -10.75	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP -0.79, phastCons 0.99
Regional constraint	o/e 0.97	unconstrained · MANE · 2,212 bp · p 0.62 · regional, not allelic
Overall
CADD	16.16	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 6.2e-05%

Overall 6.2e-05% 1/1,614,112 alleles · very rare exomes 1/1,461,808 · genomes 0/152,304 · joint denominator

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.Pro275Ser
Coding: c.823C>T
MANE Select: NM_002087
dbSNP: rs2510056489
Type: single nucleotide variant
Location: chr17:44351151 (GRCh38)
Gene constraint: LOEUF 0.59 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 76.74 · 8 PDB
Residue 275: a UniProt-annotated variant site (in)

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.Pro275His Uncertain significance ★ ⚠ same residue
GRN p.Pro275Leu Uncertain significance ★ ⚠ 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-pro275ser (accessed [today's date]).

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