Is RTN3 p.Ala2Val (c.5C>T) pathogenic?

RTN3 p.Ala2Val (c.5C>T) is classified Uncertain significance in RTN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-12). AlphaMissense: likely pathogenic (0.721); Very rare (popmax 0.00951%, afr).

How common is RTN3 p.Ala2Val (c.5C>T) in the general population?

RTN3 p.Ala2Val (c.5C>T) is very rare (popmax 0.00951%, afr) (gnomAD).

What do computational predictors say about RTN3 p.Ala2Val (c.5C>T)?

AlphaMissense predicts likely pathogenic (score 0.721) — an in-silico prediction, not a clinical call.

RTN3 p.Ala2Val

c.5C>T · rs751305965 · VCV2318261

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.721 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00951%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.721	likely pathogenic · top 10% in RTN3
REVEL	0.106	moderately benign-leaning
SaProt	LLR -8.65	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 5.8	GERP 1.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 68 kb · p 0.037 · regional, not allelic
Overall
CADD	24.2	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 0.00951% African / African-American · 7/73,628 alleles

Filtering AF 0.00444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00313%

Overall 0.00126% 20/1,591,320 alleles · very rare exomes 16/1,439,068 · genomes 4/152,252 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00951%	10,518
Finnishnot grpmax-eligible	0.00157%	63,650
European (non-Finnish)	0.00103%	97,279

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: RTN3
Protein: p.Ala2Val
Coding: c.5C>T
MANE Select: NM_001265589
dbSNP: rs751305965
Type: single nucleotide variant
Location: chr11:63681641 (GRCh38)
Gene constraint: LOEUF 0.712 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 43.42 · 1 PDB
Residue 2: the 'disordered' region; a modified residue (n-acetylalanine)

Full RTN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RTN3 p.Ser10= Benign ★★ same type
RTN3 p.Ala198Thr Uncertain significance ★ ⚠ same type
RTN3 p.Ala256Thr Uncertain significance ★ ⚠ same type
RTN3 p.Ala321Val Uncertain significance ★ ⚠ same type
RTN3 p.Ala448Gly Uncertain significance ★ ⚠ same type
RTN3 p.Ala510Pro Uncertain significance ★ ⚠ same type
RTN3 p.Ala657Val Uncertain significance ★ ⚠ same type
RTN3 p.Ala676Val 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/rtn3-p-ala2val (accessed [today's date]).

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