Is RTN2 p.Val404Met (c.1210G>A) pathogenic?

RTN2 p.Val404Met (c.1210G>A) is classified Uncertain significance in RTN2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-08-24). AlphaMissense: ambiguous (0.3453); Ultra-rare (popmax 0.0111%, amr); Associated with Inborn genetic diseases.

What condition is associated with RTN2 p.Val404Met (c.1210G>A)?

RTN2 p.Val404Met (c.1210G>A) is associated with Inborn genetic diseases, hereditary spastic paraplegia (ClinVar).

How common is RTN2 p.Val404Met (c.1210G>A) in the general population?

RTN2 p.Val404Met (c.1210G>A) is ultra-rare (popmax 0.0111%, amr) (gnomAD).

What do computational predictors say about RTN2 p.Val404Met (c.1210G>A)?

AlphaMissense predicts ambiguous (score 0.3453) — an in-silico prediction, not a clinical call.

RTN2 p.Val404Met

c.1210G>A · rs200512597 · VCV448170

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.3453 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3453	ambiguous
REVEL	0.137	moderately benign-leaning
SaProt	LLR -8.69	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -0.53, phastCons 0.78
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.23 · regional, not allelic
Overall
CADD	23.2	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 0.0111% Admixed American · 6/54,254 alleles

Filtering AF 0.00545% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00504%

Overall 0.00651% 103/1,581,130 alleles · ultra-rare exomes 88/1,428,976 · genomes 15/152,154 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0212%	4,717
Admixed Americangrpmax	0.0111%	9,042
European (non-Finnish)	0.0067%	14,925
African / African-American	0.00538%	18,597
East Asian	0.00232%	43,152
South Asian	0.00116%	86,258

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.Val404Met
Coding: c.1210G>A
MANE Select: NM_005619
dbSNP: rs200512597
Type: single nucleotide variant
Location: chr19:45489377 (GRCh38)
Gene constraint: LOEUF 0.748 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.99
Residue 404: 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

Also linked: hereditary spastic paraplegia

Similar variants

RTN2 p.Arg406Trp Uncertain significance ★★ ⚠ same condition
RTN2 p.Arg496Gln Uncertain significance ★★ ⚠ same condition
RTN2 p.Arg85Cys 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-val404met (accessed [today's date]).

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