Is RTN2 p.Pro113Ser (c.337C>T) pathogenic?

RTN2 p.Pro113Ser (c.337C>T) is classified Uncertain significance in RTN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-04). AlphaMissense: likely pathogenic (0.681); Very rare (popmax 0.00695%, nfe); Associated with Inborn genetic diseases.

What condition is associated with RTN2 p.Pro113Ser (c.337C>T)?

RTN2 p.Pro113Ser (c.337C>T) is associated with Inborn genetic diseases (ClinVar).

How common is RTN2 p.Pro113Ser (c.337C>T) in the general population?

RTN2 p.Pro113Ser (c.337C>T) is very rare (popmax 0.00695%, nfe) (gnomAD).

What do computational predictors say about RTN2 p.Pro113Ser (c.337C>T)?

AlphaMissense predicts likely pathogenic (score 0.681) — an in-silico prediction, not a clinical call.

RTN2 p.Pro113Ser

c.337C>T · rs757996406 · VCV2066850

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.681 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00695%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.681	likely pathogenic
REVEL	0.295	indeterminate
SaProt	LLR -4.92	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.23 · regional, not allelic
Overall
CADD	26.6	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 0.00695% European (non-Finnish) · 82/1,179,982 alleles

Filtering AF 0.00571% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00525%

Overall 0.00522% 84/1,610,432 alleles · very rare exomes 83/1,458,250 · genomes 1/152,182 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00695%	14,390
Admixed American	0.00167%	59,996
Remaining individualsnot grpmax-eligible	0.0016%	62,452

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.Pro113Ser
Coding: c.337C>T
MANE Select: NM_005619
dbSNP: rs757996406
Type: single nucleotide variant
Location: chr19:45494748 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 113: a UniProt-annotated variant site (in hmnr11; likely pathogenic); a UniProt-annotated variant site (in spg12; likely pathogenic); a UniProt-annotated variant site (in spg12; uncertain significance); the 'disordered' region

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.Pro113Thr Uncertain significance ★ ⚠ same residue
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

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-pro113ser (accessed [today's date]).

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