Is RTN4 p.Ala76= (c.228G>A) pathogenic?

RTN4 p.Ala76= (c.228G>A) is classified Likely benign in RTN4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-01). Rare (popmax 0.911%, nfe).

How common is RTN4 p.Ala76= (c.228G>A) in the general population?

RTN4 p.Ala76= (c.228G>A) is rare (popmax 0.911%, nfe) (gnomAD).

RTN4 p.Ala76=

c.228G>A · rs202244693 · VCV2650943

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.911%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.2	GERP -2.4
Overall
CADD	9.69	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.911% European (non-Finnish) · 10,077/1,105,606 alleles

Filtering AF 0.897% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.89%

Overall 0.779% 11,277/1,447,902 alleles · rare exomes 10,414/1,295,956 · genomes 863/151,946 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	2.2%	45
Finnishnot grpmax-eligible	1.75%	57
European (non-Finnish)grpmax	0.911%	110
Remaining individualsnot grpmax-eligible	0.431%	232
Admixed American	0.18%	554
African / African-American	0.157%	637
Ashkenazi Jewishnot grpmax-eligible	0.0218%	4,585

Amish 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: RTN4
Protein: p.Ala76=
Coding: c.228G>A
MANE Select: NM_020532
dbSNP: rs202244693
Type: single nucleotide variant
Location: chr2:55050073 (GRCh38)
Gene constraint: LOEUF 0.546 · pLI 0.38 (gnomAD)
Structure: AlphaFold pLDDT 40.92 · 2 PDB
Residue 76: the 'disordered' region

Full RTN4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RTN4 p.Glu899Gln Benign ★★ same type
RTN4 p.Gly1070Ala Likely benign ★★ same type
RTN4 p.Leu620= Benign ★★ same type
RTN4 p.Leu814Met Likely benign ★★ same type
RTN4 p.Pro992= Benign ★★ same type
RTN4 p.Ser440Asn Benign ★★ same type
RTN4 p.Ser920Cys Benign ★★ same type
RTN4 p.Thr450Met Benign ★★ 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/rtn4-p-ala76 (accessed [today's date]).

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