Is RTN2 p.Asp418Glu (c.1254T>A) pathogenic?

RTN2 p.Asp418Glu (c.1254T>A) is classified Uncertain significance in RTN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-09). AlphaMissense: ambiguous (0.4556); Ultra-rare (popmax 0.0117%, amr); Associated with Inborn genetic diseases.

What condition is associated with RTN2 p.Asp418Glu (c.1254T>A)?

RTN2 p.Asp418Glu (c.1254T>A) is associated with Inborn genetic diseases (ClinVar).

How common is RTN2 p.Asp418Glu (c.1254T>A) in the general population?

RTN2 p.Asp418Glu (c.1254T>A) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about RTN2 p.Asp418Glu (c.1254T>A)?

AlphaMissense predicts ambiguous (score 0.4556) — an in-silico prediction, not a clinical call.

RTN2 p.Asp418Glu

c.1254T>A · rs983048029 · VCV2174846

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4556 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4556	ambiguous
REVEL	0.302	indeterminate
SaProt	LLR -7.99	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.81	GERP -3.6
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.23 · regional, not allelic
Overall
CADD	16.81	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 0.0117% Admixed American · 7/59,732 alleles

Filtering AF 0.00546% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00382%

Overall 0.00062% 10/1,611,652 alleles · ultra-rare exomes 8/1,459,460 · genomes 2/152,192 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,533
Remaining individualsnot grpmax-eligible	0.00321%	31,190
European (non-Finnish)	8.48e-05%	1,179,126

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.Asp418Glu
Coding: c.1254T>A
MANE Select: NM_005619
dbSNP: rs983048029
Type: single nucleotide variant
Location: chr19:45488974 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 418: 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.Asp418= 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.Gln512Arg Uncertain significance ★★ ⚠ same condition
RTN2 p.Glu169Lys Uncertain significance ★★ ⚠ same condition
RTN2 p.Glu249Lys 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-asp418glu (accessed [today's date]).

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