Is RTN4IP1 p.Pro38Ser (c.112C>T) pathogenic?

RTN4IP1 p.Pro38Ser (c.112C>T) is classified Uncertain significance in RTN4IP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-31). AlphaMissense: likely benign (0.0754); Ultra-rare (popmax 0.011%, nfe); Associated with Inborn genetic diseases.

What condition is associated with RTN4IP1 p.Pro38Ser (c.112C>T)?

RTN4IP1 p.Pro38Ser (c.112C>T) is associated with Inborn genetic diseases (ClinVar).

How common is RTN4IP1 p.Pro38Ser (c.112C>T) in the general population?

RTN4IP1 p.Pro38Ser (c.112C>T) is ultra-rare (popmax 0.011%, nfe) (gnomAD).

What do computational predictors say about RTN4IP1 p.Pro38Ser (c.112C>T)?

AlphaMissense predicts likely benign (score 0.0754) — an in-silico prediction, not a clinical call.

RTN4IP1 p.Pro38Ser

c.112C>T · rs748829386 · VCV1387943

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0754 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0754	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -4.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.27	GERP 0.022, phastCons 0.15
Regional constraint	o/e 0.87	unconstrained · MANE · 57 kb · p 0.005 · regional, not allelic
Overall
CADD	6.862	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 0.011% European (non-Finnish) · 130/1,179,808 alleles

Filtering AF 0.00944% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00888%

Overall 0.0083% 134/1,613,796 alleles · ultra-rare exomes 129/1,461,656 · genomes 5/152,140 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.011%	9,075
Remaining individualsnot grpmax-eligible	0.0048%	20,827
African / African-American	0.00133%	74,918

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.Pro38Ser
Coding: c.112C>T
MANE Select: NM_032730
dbSNP: rs748829386
Type: single nucleotide variant
Location: chr6:106628910 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RTN4IP1 p.Pro38= Benign ★★ same residue
RTN4IP1 p.Pro38His Uncertain significance ★ ⚠ same residue
RTN4IP1 c.496-3T>C Uncertain significance ★★ same condition
RTN4IP1 p.Ala230Gly Uncertain significance ★★ ⚠ same condition
RTN4IP1 p.Ala249Thr Uncertain significance ★★ same condition
RTN4IP1 p.Ala345Pro Uncertain significance ★★ ⚠ same condition
RTN4IP1 p.Ala80Gly Uncertain significance ★★ ⚠ same condition
RTN4IP1 p.Arg10Lys 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/rtn4ip1-p-pro38ser (accessed [today's date]).

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