Is RTN4 p.Ser920Cys (c.2759C>G) pathogenic?

RTN4 p.Ser920Cys (c.2759C>G) is classified Benign in RTN4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-08-16). AlphaMissense: likely benign (0.0958); Low-frequency (popmax 3.03%, afr).

How common is RTN4 p.Ser920Cys (c.2759C>G) in the general population?

RTN4 p.Ser920Cys (c.2759C>G) is low-frequency (popmax 3.03%, afr) (gnomAD).

What do computational predictors say about RTN4 p.Ser920Cys (c.2759C>G)?

AlphaMissense predicts likely benign (score 0.0958) — an in-silico prediction, not a clinical call.

RTN4 p.Ser920Cys

c.2759C>G · rs6757705 · VCV775717

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0958 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.03%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0958	likely benign
REVEL	0.131	moderately benign-leaning
SaProt	LLR -8.86	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 5.1	GERP 1.2, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 77 kb · p 3e-13 · regional, not allelic
Overall
CADD	23.9	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 3.03% African / African-American · 2,270/75,034 alleles

Filtering AF 2.92% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.88%

Overall 0.155% 2,506/1,613,962 alleles · low-frequency exomes 1,162/1,461,650 · genomes 1,344/152,312 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.03%	33
Middle Eastern	0.214%	466
Remaining individualsnot grpmax-eligible	0.171%	584
Admixed American	0.145%	689
South Asian	0.00549%	18,216
European (non-Finnish)	0.00203%	49,162

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.Ser920Cys
Coding: c.2759C>G
MANE Select: NM_020532
dbSNP: rs6757705
Type: single nucleotide variant
Location: chr2:55025340 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.38 (gnomAD)
Structure: AlphaFold pLDDT 40.92 · 2 PDB
Residue 920: a UniProt-annotated variant site (in)

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

Similar variants

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.Thr450Met Benign ★★ same type
RTN4 p.Ala1046Ser Uncertain significance ★ 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-ser920cys (accessed [today's date]).

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