# NM_002087.4(GRN):c.182G>A (p.Cys61Tyr)

https://sugi.bio/variant/grn-p-cys61tyr

## Summary

**GRN p.Cys61Tyr (c.182G>A)** is classified **Uncertain significance** in GRN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-25). AlphaMissense: likely pathogenic (0.6707); Absent from gnomAD v4.1; Associated with neuronal ceroid lipofuscinosis 11.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2510054490 · 1 submitter · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the GRN gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to neuronal ceroid lipofuscinosis 11.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Age of onset (of this condition) | Adolescent, Infancy |
| Diagnostic panels | GRN is a diagnostic-grade gene on 16 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017426/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GRN](https://sugi.bio/atlas/gene/GRN/) |
| Protein change (HGVS p.) | p.Cys61Tyr |
| Coding change (HGVS c.) | c.182G>A |
| MANE Select transcript | [NM_002087](https://www.ncbi.nlm.nih.gov/nuccore/NM_002087) |
| dbSNP | [rs2510054490](https://www.ncbi.nlm.nih.gov/snp/rs2510054490/) |
| Variant type | single nucleotide variant |
| Location | chr17:44349469-44349469 (GRCh38) |
| ClinVar | [VCV2092824](https://www.ncbi.nlm.nih.gov/clinvar/variation/2092824/) |

**All HGVS expressions:** `LRG_661:g.9347G>A`, `LRG_661t1:c.182G>A`, `NC_000017.10:g.42426837G>A`, `NC_000017.11:g.44349469G>A`, `NG_007886.1:g.9347G>A`, `NM_002087.4:c.182G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.6707)
- REVEL 0.654 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -14.94 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 9.969, GERP 1.21, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.7**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.97** across the covering region of the MANE Select transcript (44,349,165–44,351,377), spanning 2,212 bp. Chi-square p 0.62. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.27 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**GRN** population constraint: LOEUF 0.59, pLI 0.042667, missense-Z 1.301. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **neuronal ceroid lipofuscinosis** — Definitive (AR)
- **frontotemporal dementia and/or amyotrophic lateral sclerosis** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 76.74, 20% of residues very-high.

**8 experimental structure(s)** (PDB): [1G26](https://www.rcsb.org/structure/1G26), [2JYE](https://www.rcsb.org/structure/2JYE), [2JYT](https://www.rcsb.org/structure/2JYT), [2JYU](https://www.rcsb.org/structure/2JYU), [2JYV](https://www.rcsb.org/structure/2JYV), [6NUG](https://www.rcsb.org/structure/6NUG).

## What this gene does {#gene-function}

*Describes the biological roles of GRN (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** GRN's established molecular role includes RNA binding.


### Pathways affected {#pathways}

GRN participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** RNA binding, protein-folding chaperone binding.

**Biological process:** lysosomal transport, lysosomal lumen acidification, positive regulation of cell migration, negative regulation of neuron apoptotic process, positive regulation of epithelial cell proliferation, protein stabilization.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-07-25.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-07-25 |

## Associated conditions {#conditions}

[neuronal ceroid lipofuscinosis 11](https://sugi.bio/atlas/disease/neuronal-ceroid-lipofuscinosis-11/), [GRN-related frontotemporal lobar degeneration with Tdp43 inclusions](https://sugi.bio/atlas/disease/grn-related-frontotemporal-lobar-degeneration-with-tdp43-inclusions/).

**Reported phenotype names (ClinVar):** Neuronal ceroid lipofuscinosis 11, GRN-related frontotemporal lobar degeneration with Tdp43 inclusions, GRN-Related Neuronal Ceroid-Lipofuscinosis, DEMENTIA, HEREDITARY DYSPHASIC DISINHIBITION, FRONTOTEMPORAL LOBAR DEGENERATION WITH UBIQUITIN-POSITIVE INCLUSIONS, FTLD-TDP, GRN-RELATED, GRN Frontotemporal Dementia, FRONTOTEMPORAL DEMENTIA WITH TDP43 INCLUSIONS, GRN-RELATED.

## Same-residue context {#hotspot}

Residue **61** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [GRN p.Cys61fs](/variant/grn-p-cys61fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related GRN variant pages (same residue, condition, or type): [GRN p.Cys61fs](/variant/grn-p-cys61fs), [GRN c.1414-1G>T](/variant/grn-c-1414-minus-1g-t), [GRN c.1414-2A>G](/variant/grn-c-1414-minus-2a-g), [GRN c.264+1G>A](/variant/grn-c-264-plus-1g-a), [GRN c.349+1G>C](/variant/grn-c-349-plus-1g-c), [GRN c.599-1G>A](/variant/grn-c-599-minus-1g-a), [GRN c.709-1G>A](/variant/grn-c-709-minus-1g-a), [GRN c.709-2A>G](/variant/grn-c-709-minus-2a-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2092824). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*