# NM_006493.4(CLN5):c.1045C>T (p.Pro349Ser)

https://sugi.bio/variant/cln5-p-pro349ser

## Summary

**CLN5 p.Pro349Ser (c.1045C>T)** is classified **Uncertain significance** in CLN5 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-10-30). AlphaMissense: likely pathogenic (0.6104); Ultra-rare (popmax 0.0214%, nfe); Associated with neuronal ceroid lipofuscinosis.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs41287036 · 9 submitters · 2 linked conditions · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0214%, nfe)

## For patients & families {#patients}

This is a change in the CLN5 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 9 submitters, and is linked to neuronal ceroid lipofuscinosis.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 7 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010739/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CLN5](https://sugi.bio/atlas/gene/CLN5/) |
| Protein change (HGVS p.) | p.Pro349Ser |
| Coding change (HGVS c.) | c.1045C>T |
| MANE Select transcript | [NM_006493](https://www.ncbi.nlm.nih.gov/nuccore/NM_006493) |
| dbSNP | [rs41287036](https://www.ncbi.nlm.nih.gov/snp/rs41287036/) |
| Variant type | single nucleotide variant |
| Location | chr13:77000937-77000937 (GRCh38) |
| ClinVar | [VCV128780](https://www.ncbi.nlm.nih.gov/clinvar/variation/128780/) |

**All HGVS expressions:** `LRG_692:g.14014C>T`, `LRG_692t1:c.1192C>T`, `NC_000013.10:g.77575072C>T`, `NC_000013.11:g.77000937C>T`, `NG_009064.1:g.14014C>T`, `NM_001366624.2:c.*494C>T`, `NM_006493.4:c.1045C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6104)
- REVEL 0.878 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.9 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 4.865, GERP 1.78, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 24.0**. 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.*
- Regional missense constraint: **o/e 0.97** across the covering region of the MANE Select transcript (76,992,099–77,000,966), spanning 8,867 bp. Chi-square p 0.55. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0214%** (nfe) · FAF95 0.0192% · FAF99 0.0184% · 252/1,175,898 in the highest group · 277/1,604,766 alleles overall — ultra-rare (popmax 0.0214%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 1.86% | 54 |
| European (non-Finnish) (grpmax) | 0.0214% | 4,666 |
| African / African-American | 0.00536% | 18,671 |
| Remaining individuals (not grpmax-eligible) | 0.00482% | 20,750 |
| Admixed American | 0.00169% | 59,310 |

Amish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**CLN5** population constraint: LOEUF 1.197, pLI 3.9441e-10, missense-Z 0.27528. *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 83.05, 65% of residues very-high.

**1 experimental structure(s)** (PDB): [6R99](https://www.rcsb.org/structure/6R99).

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

*Describes the biological roles of CLN5 (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:** CLN5's established molecular role includes D-mannose binding.


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

**Molecular function:** D-mannose binding, long-chain fatty acyl-CoA hydrolase activity, bis(monoacylglycero)phosphate synthase activity.

**Biological process:** obsolete signal peptide processing, lysosomal lumen acidification, brain development, neurogenesis, retrograde transport, endosome to Golgi, positive regulation of GTP binding.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-30.

**Submitter consensus:** unanimous (9/9 Uncertain significance).

**Submission history:** 9 submissions (2014–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-04-16 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-01 |
| Genetic Services Laboratory, University of Chicago | Uncertain significance | criteria provided, single submitter | clinical testing | 2014-01-14 |
| Genome-Nilou Lab | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-09-05 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-09-27 |
| Geisinger Autism and Developmental Medicine Institute, Geisinger Health System | Uncertain significance | criteria provided, single submitter | provider interpretation | 2018-02-21 |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-30 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-18 |

## Associated conditions {#conditions}

[neuronal ceroid lipofuscinosis](https://sugi.bio/atlas/disease/neuronal-ceroid-lipofuscinosis/), [neuronal ceroid lipofuscinosis 5](https://sugi.bio/atlas/disease/neuronal-ceroid-lipofuscinosis-5/).

**Reported phenotype names (ClinVar):** Neuronal ceroid lipofuscinosis, not provided, Neuronal ceroid lipofuscinosis 5, none provided, Neuronal Ceroid Lipofuscinoses, Neuronal ceroid lipofuscinosis Finnish variant, NEURONAL CEROID LIPOFUSCINOSIS, LATE INFANTILE, FINNISH VARIANT, CLN5-Related Neuronal Ceroid-Lipofuscinosis, CEROID LIPOFUSCINOSIS, NEURONAL, 5, VARIABLE AGE AT ONSET.

## Similar variants {#similar}

Related CLN5 variant pages (same residue, condition, or type): [CLN5 p.Pro349=](/variant/cln5-p-pro349), [CLN5 c.174-2A>G](/variant/cln5-c-174-minus-2a-g), [CLN5 p.Arg150Ter](/variant/cln5-p-arg150ter), [CLN5 p.Arg63His](/variant/cln5-p-arg63his), [CLN5 p.Arg96Ter](/variant/cln5-p-arg96ter), [CLN5 p.Asn143Ser](/variant/cln5-p-asn143ser), [CLN5 p.Cys144Tyr](/variant/cln5-p-cys144tyr), [CLN5 p.Cys77Tyr](/variant/cln5-p-cys77tyr).

### 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 128780). 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.*