Is RTN4IP1 p.Pro38= (c.114T>A) pathogenic?

RTN4IP1 p.Pro38= (c.114T>A) is classified Benign in RTN4IP1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). Common (popmax 60.3%, eas) — too common for a highly-penetrant pathogenic allele; Associated with optic atrophy 10 with or without ataxia, intellectual disability, and seizures.

What condition is associated with RTN4IP1 p.Pro38= (c.114T>A)?

RTN4IP1 p.Pro38= (c.114T>A) is associated with optic atrophy 10 with or without ataxia, intellectual disability, and seizures (ClinVar).

RTN4IP1 p.Pro38=

Q: How common is RTN4IP1 p.Pro38= (c.114T>A) in the general population?

RTN4IP1 p.Pro38= (c.114T>A) is common (popmax 60.3%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.114T>A · rs1987623 · VCV1170261

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 60.3%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

optic atrophy 10 with or without ataxia, intellectual disability, and seizures

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 -3	GERP -5.8
Overall
CADD	3.588	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 60.3% East Asian · 27,049/44,842 alleles

Filtering AF 59.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 59.5%

Overall 30.9% 499,034/1,613,432 alleles · common exomes 438,978/1,461,516 · genomes 60,056/151,916 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	60.3%	2
African / African-American	58%	2
Admixed American	48.9%	2
Finnishnot grpmax-eligible	35%	3
Remaining individualsnot grpmax-eligible	32.4%	3
Middle Eastern	30.4%	3
European (non-Finnish)	27.5%	4
Amishnot grpmax-eligible	25.8%	4
South Asian	25%	4
Ashkenazi Jewishnot grpmax-eligible	23.6%	4

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: RTN4IP1
Protein: p.Pro38=
Coding: c.114T>A
MANE Select: NM_032730
dbSNP: rs1987623
Type: single nucleotide variant
Location: chr6:106628908 (GRCh38)
Gene constraint: LOEUF 0.952 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.54 · 1 PDB

Full RTN4IP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

optic atrophy 10 with or without ataxia, intellectual disability, and seizures — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RTN4IP1 p.Pro38Ser Uncertain significance ★★ ⚠ same residue
RTN4IP1 p.Pro38His Uncertain significance ★ ⚠ same residue
RTN4IP1 c.806+1G>A Pathogenic ★★ same condition
RTN4IP1 p.Arg103His Pathogenic ★★ same condition
RTN4IP1 p.Lys201Ter Pathogenic ★★ same condition
RTN4IP1 p.Trp20Ter Pathogenic/Likely pathogenic ★★ same condition
RTN4IP1 p.Pro85Leu Uncertain significance ★★ ⚠ same condition
RTN4IP1 c.495+27A>G Benign ★★ 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/rtn4ip1-p-pro38 (accessed [today's date]).

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