Is RTN3 p.Leu72Val (c.214C>G) pathogenic?

RTN3 p.Leu72Val (c.214C>G) is classified Uncertain significance in RTN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely benign (0.0944); Ultra-rare (popmax 0.0177%, afr).

How common is RTN3 p.Leu72Val (c.214C>G) in the general population?

RTN3 p.Leu72Val (c.214C>G) is ultra-rare (popmax 0.0177%, afr) (gnomAD).

What do computational predictors say about RTN3 p.Leu72Val (c.214C>G)?

AlphaMissense predicts likely benign (score 0.0944) — an in-silico prediction, not a clinical call.

RTN3 p.Leu72Val

c.214C>G · VCV4157905

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0944 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0177%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0944	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -6.61	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 0.36	GERP -3.8, phastCons 0.98
Regional constraint	o/e 1.07	unconstrained · MANE · 68 kb · p 0.037 · regional, not allelic
Overall
CADD	19.53	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 0.0177% African / African-American · 13/73,404 alleles

Filtering AF 0.0105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00828%

Overall 0.00107% 17/1,587,618 alleles · ultra-rare exomes 14/1,435,342 · genomes 3/152,276 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0177%	5,646
Middle Eastern	0.017%	5,896
Remaining individualsnot grpmax-eligible	0.00163%	61,318
South Asian	0.00117%	85,126
European (non-Finnish)	8.54e-05%	1,171,558

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.Leu72Val
Coding: c.214C>G
MANE Select: NM_001265589
Type: single nucleotide variant
Location: chr11:63718716 (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-leu72val (accessed [today's date]).

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