Is RTN2 p.Leu320Pro (c.959T>C) pathogenic?

RTN2 p.Leu320Pro (c.959T>C) is classified Conflicting classifications of pathogenicity in RTN2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-10-02). AlphaMissense: likely benign (0.0575); Very rare (popmax 0.00517%, nfe); Associated with Inborn genetic diseases.

What condition is associated with RTN2 p.Leu320Pro (c.959T>C)?

RTN2 p.Leu320Pro (c.959T>C) is associated with Inborn genetic diseases (ClinVar).

How common is RTN2 p.Leu320Pro (c.959T>C) in the general population?

RTN2 p.Leu320Pro (c.959T>C) is very rare (popmax 0.00517%, nfe) (gnomAD).

What do computational predictors say about RTN2 p.Leu320Pro (c.959T>C)?

AlphaMissense predicts likely benign (score 0.0575) — an in-silico prediction, not a clinical call.

RTN2 p.Leu320Pro

c.959T>C · rs138317158 · VCV2143057

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0575 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00517%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0575	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -5.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP 0.89, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.23 · regional, not allelic
Overall
CADD	18.96	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00517% European (non-Finnish) · 61/1,180,028 alleles

Filtering AF 0.0041% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.00403% 65/1,613,804 alleles · very rare exomes 56/1,461,594 · genomes 9/152,210 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00517%	19,345
Admixed American	0.00334%	29,981
Remaining individualsnot grpmax-eligible	0.0032%	31,231

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: RTN2
Protein: p.Leu320Pro
Coding: c.959T>C
MANE Select: NM_005619
dbSNP: rs138317158
Type: single nucleotide variant
Location: chr19:45493234 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 320: a UniProt-annotated variant site (in hmnr11; likely pathogenic); a UniProt-annotated variant site (in spg12; likely pathogenic)

Full RTN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RTN2 p.Arg406Trp Uncertain significance ★★ ⚠ same condition
RTN2 p.Arg496Gln Uncertain significance ★★ ⚠ same condition
RTN2 p.Arg91His Uncertain significance ★★ ⚠ same condition
RTN2 p.Asn177Ser Uncertain significance ★★ ⚠ same condition
RTN2 p.Asp418Glu Uncertain significance ★★ same condition
RTN2 p.Gln512Arg Uncertain significance ★★ ⚠ same condition
RTN2 p.Glu169Lys Uncertain significance ★★ ⚠ same condition
RTN2 p.Glu249Lys Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/rtn2-p-leu320pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown