Is RTN4 p.Ser203Cys (c.608C>G) pathogenic?

RTN4 p.Ser203Cys (c.608C>G) is classified Uncertain significance in RTN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-16). AlphaMissense: likely benign (0.2065); Ultra-rare (popmax 0.0151%, amr).

How common is RTN4 p.Ser203Cys (c.608C>G) in the general population?

RTN4 p.Ser203Cys (c.608C>G) is ultra-rare (popmax 0.0151%, amr) (gnomAD).

What do computational predictors say about RTN4 p.Ser203Cys (c.608C>G)?

AlphaMissense predicts likely benign (score 0.2065) — an in-silico prediction, not a clinical call.

RTN4 p.Ser203Cys

c.608C>G · rs201780227 · VCV2405940

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2065 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0151%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2065	likely benign
REVEL	0.307	indeterminate
SaProt	LLR -9.33	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 77 kb · p 3e-13 · regional, not allelic
Overall
CADD	30.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0151% Admixed American · 9/59,726 alleles

Filtering AF 0.00776% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00581%

Overall 0.00273% 44/1,612,650 alleles · ultra-rare exomes 41/1,460,476 · genomes 3/152,174 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0151%	6,636
Remaining individualsnot grpmax-eligible	0.0032%	31,209
European (non-Finnish)	0.0028%	35,737

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.Ser203Cys
Coding: c.608C>G
MANE Select: NM_020532
dbSNP: rs201780227
Type: single nucleotide variant
Location: chr2:55028169 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.38 (gnomAD)
Structure: AlphaFold pLDDT 40.92 · 2 PDB
Residue 203: the 'disordered' region

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

Similar variants

RTN4 p.Ser203Phe 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
RTN4 p.Ser920Cys 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-ser203cys (accessed [today's date]).

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