# NM_005619.5(RTN2):c.1506C>T (p.Ile502=)

https://sugi.bio/variant/rtn2-p-ile502

## Summary

**RTN2 p.Ile502= (c.1506C>T)** is classified **Likely benign** in RTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-14). Ultra-rare (popmax 0.055%, amr); Associated with Spastic paraplegia.

**At a glance:** Likely benign · review: Single submitter · rsID rs780045639 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.055%, amr)

## For patients & families {#patients}

This is a change in the RTN2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Spastic paraplegia.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RTN2](https://sugi.bio/atlas/gene/RTN2/) |
| Protein change (HGVS p.) | p.Ile502= |
| Coding change (HGVS c.) | c.1506C>T |
| MANE Select transcript | [NM_005619](https://www.ncbi.nlm.nih.gov/nuccore/NM_005619) |
| dbSNP | [rs780045639](https://www.ncbi.nlm.nih.gov/snp/rs780045639/) |
| Variant type | single nucleotide variant |
| Location | chr19:45486105-45486105 (GRCh38) |
| ClinVar | [VCV2069241](https://www.ncbi.nlm.nih.gov/clinvar/variation/2069241/) |

**All HGVS expressions:** `NC_000019.10:g.45486105G>A`, `NC_000019.9:g.45989363G>A`, `NG_032157.1:g.15949C>T`, `NM_005619.5:c.1506C>T`, `NM_206900.3:c.1287C>T`, `NM_206901.3:c.486C>T`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -3.294, GERP -3.91 — fast-evolving / accelerated position
- CADD: **PHRED 2.85**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.22 donor loss), 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 (gnomAD v4.1): grpmax **0.055%** (amr) · FAF95 0.0402% · FAF99 0.0351% · 33/59,970 in the highest group · 37/1,613,840 alleles overall — ultra-rare (popmax 0.055%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.055% | 1,817 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,476 |
| European (non-Finnish) | 0.000254% | 393,312 |

*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}

**RTN2** population constraint: LOEUF 0.748, pLI 4.9773e-06, missense-Z 0.74227. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **502** lies in a UniProt-annotated variant site (in hmnr11; likely pathogenic); a UniProt-annotated variant site (in spg12; likely pathogenic); the reticulon domain.

AlphaFold model confidence (whole protein): pLDDT 50.99, 0% of residues very-high.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-01-14.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-01-14 |

## Associated conditions {#conditions}

[Spastic paraplegia](https://sugi.bio/atlas/disease/spastic-paraplegia/).

**Reported phenotype names (ClinVar):** Spastic paraplegia.

## Similar variants {#similar}

Related RTN2 variant pages (same residue, condition, or type): [RTN2 p.Glu50Ter](/variant/rtn2-p-glu50ter), [RTN2 c.1497+3G>A](/variant/rtn2-c-1497-plus-3g-a), [RTN2 p.Ala529Thr](/variant/rtn2-p-ala529thr), [RTN2 p.Arg152Pro](/variant/rtn2-p-arg152pro), [RTN2 p.Arg252Trp](/variant/rtn2-p-arg252trp), [RTN2 p.Arg398Cys](/variant/rtn2-p-arg398cys), [RTN2 p.Arg447Gln](/variant/rtn2-p-arg447gln), [RTN2 p.Arg496Trp](/variant/rtn2-p-arg496trp).

### 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 2069241). 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.*