Is RTN2 p.Ser65Phe (c.194C>T) pathogenic?

RTN2 p.Ser65Phe (c.194C>T) is classified Uncertain significance in RTN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-15). AlphaMissense: likely pathogenic (0.9392); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with RTN2 p.Ser65Phe (c.194C>T)?

RTN2 p.Ser65Phe (c.194C>T) is associated with Inborn genetic diseases (ClinVar).

How common is RTN2 p.Ser65Phe (c.194C>T) in the general population?

RTN2 p.Ser65Phe (c.194C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RTN2 p.Ser65Phe (c.194C>T)?

AlphaMissense predicts likely pathogenic (score 0.9392) — an in-silico prediction, not a clinical call.

RTN2 p.Ser65Phe

c.194C>T · rs2513743895 · VCV2261092

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9392 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9392	likely pathogenic · top 6% in RTN2
REVEL	0.367	indeterminate
SaProt	LLR -9.28	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RTN2
Protein: p.Ser65Phe
Coding: c.194C>T
MANE Select: NM_005619
dbSNP: rs2513743895
Type: single nucleotide variant
Location: chr19:45494891 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 65: a UniProt-annotated variant site (in hmnr11; likely pathogenic); a UniProt-annotated variant site (in spg12; likely pathogenic); 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.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-ser65phe (accessed [today's date]).

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