# NM_001042432.2(CLN3):c.1056G>A (p.Gln352=)

https://sugi.bio/variant/cln3-p-gln352

## Summary

**CLN3 p.Gln352= (c.1056G>A)** is classified **Uncertain significance** in CLN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-01). Absent from gnomAD v4.1; Associated with retinitis pigmentosa.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CLN3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to retinitis pigmentosa.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, Mitochondrial inheritance |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-5 / 10 000 (Europe) |
| Clinical trials | 238 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CLN3 is a diagnostic-grade gene on 13 Genomics England panels |

**Commonly reported features of Retinitis pigmentosa** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Conductive hearing impairment — Very frequent (99-80%)
- Sensorineural hearing impairment — Very frequent (99-80%)
- Visual impairment — Very frequent (99-80%)
- Abnormal electroretinogram — Very frequent (99-80%)
- Retinal degeneration — Very frequent (99-80%)
- Photophobia — Very frequent (99-80%)
- Blindness — Very frequent (99-80%)
- Nystagmus — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005694/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CLN3](https://sugi.bio/atlas/gene/CLN3/) |
| Protein change (HGVS p.) | p.Gln352= |
| Coding change (HGVS c.) | c.1056G>A |
| MANE Select transcript | [NM_001042432](https://www.ncbi.nlm.nih.gov/nuccore/NM_001042432) |
| Variant type | single nucleotide variant |
| Location | chr16:28482105-28482105 (GRCh38) |
| ClinVar | [VCV3544492](https://www.ncbi.nlm.nih.gov/clinvar/variation/3544492/) |

**All HGVS expressions:** `LRG_689:g.15198G>A`, `LRG_689t1:c.1056G>A`, `LRG_689t2:c.1056G>A`, `NC_000016.10:g.28482105C>T`, `NC_000016.9:g.28493426C>T`, `NG_008654.2:g.15198G>A`, `NM_000086.2:c.1056G>A`, `NM_001042432.2:c.1056G>A`, `NM_001286104.2:c.984G>A`, `NM_001286105.2:c.756G>A`, `NM_001286109.2:c.822G>A`, `NM_001286110.2:c.894G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.89) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.789, GERP 0.453, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 20.0**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.89**, acceptor gain **0.00**, donor gain **0.04**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.04**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.66** (loss), gain 0.24 / loss 0.66. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is 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}

**CLN3** population constraint: LOEUF 1.022, pLI 5.3225e-14, missense-Z 0.97718; ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (0–3 scale). *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)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 81.81, 55% of residues very-high.

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

*Describes the biological roles of CLN3 (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:** CLN3's established molecular role includes glycolipid binding.


### Pathways affected {#pathways}

CLN3 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Glycosphingolipid transport](https://reactome.org/content/detail/R-HSA-9845576) | curated |

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

**Molecular function:** glycolipid binding, sulfatide binding.

**Biological process:** receptor-mediated endocytosis, lysosomal lumen acidification, regulation of fibroblast migration, lysosomal lumen pH elevation, amyloid precursor protein catabolic process, negative regulation of apoptotic process.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Lab De Baere, Eye and Developmental Genetics Lab, Ghent University | Uncertain significance | criteria provided, single submitter | research | 2024-10-01 |

## Associated conditions {#conditions}

[retinitis pigmentosa](https://sugi.bio/atlas/disease/retinitis-pigmentosa/).

**Reported phenotype names (ClinVar):** Retinitis pigmentosa.

## Same-residue context {#hotspot}

Residue **352** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [CLN3 p.Gln352Ter](/variant/cln3-p-gln352ter), [CLN3 p.Gln352His](/variant/cln3-p-gln352his). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CLN3 variant pages (same residue, condition, or type): [CLN3 p.Gln352Ter](/variant/cln3-p-gln352ter), [CLN3 p.Gln352His](/variant/cln3-p-gln352his), [CLN3 p.Arg405Trp](/variant/cln3-p-arg405trp), [CLN3 p.Ser171Phe](/variant/cln3-p-ser171phe), [CLN3 p.Val330Ile](/variant/cln3-p-val330ile), [CLN3 p.Gln204Pro](/variant/cln3-p-gln204pro), [CLN3 p.Ile285Val](/variant/cln3-p-ile285val), [CLN3 p.Ser423Leu](/variant/cln3-p-ser423leu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 3544492). 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.*