# NM_005619.5(RTN2):c.1037C>T (p.Ala346Val)

https://sugi.bio/variant/rtn2-p-ala346val

## Summary

**RTN2 p.Ala346Val (c.1037C>T)** is classified **Conflicting classifications of pathogenicity** in RTN2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-08-04). AlphaMissense: likely benign (0.1185); Very rare (popmax 0.0029%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1176639498 · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.0029%, nfe)

## For patients & families {#patients}

This is a change in the RTN2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to Inborn genetic diseases.

*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.Ala346Val |
| Coding change (HGVS c.) | c.1037C>T |
| MANE Select transcript | [NM_005619](https://www.ncbi.nlm.nih.gov/nuccore/NM_005619) |
| dbSNP | [rs1176639498](https://www.ncbi.nlm.nih.gov/snp/rs1176639498/) |
| Variant type | single nucleotide variant |
| Location | chr19:45489550-45489550 (GRCh38) |
| ClinVar | [VCV1579893](https://www.ncbi.nlm.nih.gov/clinvar/variation/1579893/) |

**All HGVS expressions:** `NC_000019.10:g.45489550G>A`, `NC_000019.9:g.45992808G>A`, `NG_032157.1:g.12504C>T`, `NM_005619.3:c.1037C>T`, `NM_005619.5:c.1037C>T`, `NM_206900.3:c.818C>T`, `NM_206901.3:c.17C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1185)
- REVEL 0.073 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.391 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 3.351, GERP 0.551, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 16.5**. 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 0.95** across the covering region of the MANE Select transcript (45,485,711–45,496,825), spanning 11,114 bp. Chi-square p 0.23. 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>C, Δ0.33 acceptor 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 **0.0029%** (nfe) · FAF95 0.00209% · FAF99 0.00185% · 34/1,170,522 in the highest group · 39/1,593,648 alleles overall — very rare (popmax 0.0029%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00324% | 30,866 |
| European (non-Finnish) (grpmax) | 0.0029% | 34,427 |
| Admixed American | 0.00175% | 57,212 |
| Finnish (not grpmax-eligible) | 0.0016% | 62,568 |
| South Asian | 0.00114% | 87,716 |

Remaining individuals 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}

**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 **346** 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2023-08-04.

**Submitter consensus:** conflicting (1 Uncertain significance, 1 Likely benign).

**Submission history:** 2 submissions (2022–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-08-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-02-05 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, Spastic paraplegia.

## Similar variants {#similar}

Related RTN2 variant pages (same residue, condition, or type): [RTN2 p.Ala346=](/variant/rtn2-p-ala346), [RTN2 p.Arg406Trp](/variant/rtn2-p-arg406trp), [RTN2 p.Arg496Gln](/variant/rtn2-p-arg496gln), [RTN2 p.Arg91His](/variant/rtn2-p-arg91his), [RTN2 p.Asn177Ser](/variant/rtn2-p-asn177ser), [RTN2 p.Asp418Glu](/variant/rtn2-p-asp418glu), [RTN2 p.Gln512Arg](/variant/rtn2-p-gln512arg), [RTN2 p.Glu169Lys](/variant/rtn2-p-glu169lys).

### 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 1579893). 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.*