Is RTN3 p.His152Asp (c.454C>G) pathogenic?

RTN3 p.His152Asp (c.454C>G) is classified Uncertain significance in RTN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-26). AlphaMissense: likely benign (0.0931); Very rare (popmax 0.00333%, amr).

How common is RTN3 p.His152Asp (c.454C>G) in the general population?

RTN3 p.His152Asp (c.454C>G) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about RTN3 p.His152Asp (c.454C>G)?

AlphaMissense predicts likely benign (score 0.0931) — an in-silico prediction, not a clinical call.

RTN3 p.His152Asp

c.454C>G · VCV4580147

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0931 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0931	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -5.40	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.022	GERP -1.4, phastCons 0.001
Regional constraint	o/e 1.07	unconstrained · MANE · 68 kb · p 0.037 · regional, not allelic
Overall
CADD	2.02	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,992 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000248% 4/1,614,032 alleles · very rare exomes 1/1,461,864 · genomes 3/152,168 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,996
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	8.47e-05%	1,180,036

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.His152Asp
Coding: c.454C>G
MANE Select: NM_001265589
Type: single nucleotide variant
Location: chr11:63718956 (GRCh38)
Gene constraint: LOEUF 0.712 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 43.42 · 1 PDB

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.Ala2Val 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

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-his152asp (accessed [today's date]).

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