Is RTN2 p.Ala346Val (c.1037C>T) pathogenic?

RTN2 p.Ala346Val (c.1037C>T) is classified Conflicting classifications of pathogenicity in RTN2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-08-04). AlphaMissense: likely benign (0.1185); Very rare (popmax 0.0029%, nfe); Associated with Inborn genetic diseases.

What condition is associated with RTN2 p.Ala346Val (c.1037C>T)?

RTN2 p.Ala346Val (c.1037C>T) is associated with Inborn genetic diseases (ClinVar).

How common is RTN2 p.Ala346Val (c.1037C>T) in the general population?

RTN2 p.Ala346Val (c.1037C>T) is very rare (popmax 0.0029%, nfe) (gnomAD).

What do computational predictors say about RTN2 p.Ala346Val (c.1037C>T)?

AlphaMissense predicts likely benign (score 0.1185) — an in-silico prediction, not a clinical call.

RTN2 p.Ala346Val

c.1037C>T · rs1176639498 · VCV1579893

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1185 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0029%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1185	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -5.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.33 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.4	GERP 0.55, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.23 · regional, not allelic
Overall
CADD	16.5	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 0.0029% European (non-Finnish) · 34/1,170,522 alleles

Filtering AF 0.00209% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00185%

Overall 0.00245% 39/1,593,648 alleles · very rare exomes 35/1,441,648 · genomes 4/152,000 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00324%	30,866
European (non-Finnish)grpmax	0.0029%	34,427
Admixed American	0.00175%	57,212
Finnishnot grpmax-eligible	0.0016%	62,568
South Asian	0.00114%	87,716

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: RTN2
Protein: p.Ala346Val
Coding: c.1037C>T
MANE Select: NM_005619
dbSNP: rs1176639498
Type: single nucleotide variant
Location: chr19:45489550 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 346: a UniProt-annotated variant site (in hmnr11; likely pathogenic); a UniProt-annotated variant site (in spg12; likely pathogenic); the reticulon domain

Full RTN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RTN2 p.Ala346= Likely benign ★ same residue
RTN2 p.Arg406Trp Uncertain significance ★★ ⚠ same condition
RTN2 p.Arg496Gln Uncertain significance ★★ ⚠ same condition
RTN2 p.Arg91His Uncertain significance ★★ ⚠ same condition
RTN2 p.Asn177Ser Uncertain significance ★★ ⚠ same condition
RTN2 p.Asp418Glu Uncertain significance ★★ same condition
RTN2 p.Gln512Arg Uncertain significance ★★ ⚠ same condition
RTN2 p.Glu169Lys Uncertain significance ★★ ⚠ same condition

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/rtn2-p-ala346val (accessed [today's date]).

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