Is RTN4 p.Pro609Leu (c.1826C>T) pathogenic?

RTN4 p.Pro609Leu (c.1826C>T) is classified Uncertain significance in RTN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-05). AlphaMissense: ambiguous (0.5289); Ultra-rare (popmax 0.0713%, eas).

How common is RTN4 p.Pro609Leu (c.1826C>T) in the general population?

RTN4 p.Pro609Leu (c.1826C>T) is ultra-rare (popmax 0.0713%, eas) (gnomAD).

What do computational predictors say about RTN4 p.Pro609Leu (c.1826C>T)?

AlphaMissense predicts ambiguous (score 0.5289) — an in-silico prediction, not a clinical call.

RTN4 p.Pro609Leu

c.1826C>T · rs780367107 · VCV3157033

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5289 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0713%, eas)

Computational evidence

Protein change
AlphaMissense	0.5289	ambiguous
REVEL	0.368	indeterminate
SaProt	LLR -6.75	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 77 kb · p 3e-13 · 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 0.0713% East Asian · 32/44,880 alleles

Filtering AF 0.0519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0452%

Overall 0.00211% 34/1,613,806 alleles · ultra-rare exomes 28/1,461,680 · genomes 6/152,126 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0713%	1,403
African / African-American	0.00134%	74,896
South Asian	0.0011%	91,080

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.Pro609Leu
Coding: c.1826C>T
MANE Select: NM_020532
dbSNP: rs780367107
Type: single nucleotide variant
Location: chr2:55026273 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.38 (gnomAD)
Structure: AlphaFold pLDDT 40.92 · 2 PDB

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.Ser920Cys Benign ★★ same type
RTN4 p.Thr450Met 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-pro609leu (accessed [today's date]).

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