Is RTN4 p.Arg1189Ser (c.3565C>A) pathogenic?

RTN4 p.Arg1189Ser (c.3565C>A) is classified Uncertain significance in RTN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: likely pathogenic (0.8992); Very rare (popmax 0.000939%, nfe).

How common is RTN4 p.Arg1189Ser (c.3565C>A) in the general population?

RTN4 p.Arg1189Ser (c.3565C>A) is very rare (popmax 0.000939%, nfe) (gnomAD).

What do computational predictors say about RTN4 p.Arg1189Ser (c.3565C>A)?

AlphaMissense predicts likely pathogenic (score 0.8992) — an in-silico prediction, not a clinical call.

RTN4 p.Arg1189Ser

c.3565C>A · VCV4580179

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8992 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000939%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8992	likely pathogenic · top 7% in RTN4
REVEL	0.132	moderately benign-leaning
SaProt	LLR -8.03	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP 2.6, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 77 kb · p 3e-13 · regional, not allelic
Overall
CADD	25.5	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 0.000939% European (non-Finnish) · 11/1,172,038 alleles

Filtering AF 0.000504% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000368%

Overall 0.000686% 11/1,604,040 alleles · very rare exomes 10/1,451,906 · genomes 1/152,134 · joint denominator

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: RTN4
Protein: p.Arg1189Ser
Coding: c.3565C>A
MANE Select: NM_020532
Type: single nucleotide variant
Location: chr2:54973170 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.38 (gnomAD)
Structure: AlphaFold pLDDT 40.92 · 2 PDB
Residue 1189: the reticulon domain

Full RTN4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RTN4 p.Arg1189Cys Uncertain significance ★ ⚠ same residue
RTN4 p.Arg1189His Uncertain significance ★ same residue
RTN4 p.Glu899Gln Benign ★★ same type
RTN4 p.Gly1070Ala Likely benign ★★ same type
RTN4 p.Leu620= Benign ★★ same type
RTN4 p.Leu814Met Likely benign ★★ same type
RTN4 p.Pro992= Benign ★★ same type
RTN4 p.Ser440Asn Benign ★★ same type

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/rtn4-p-arg1189ser (accessed [today's date]).

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