Is RTN4IP1 p.Pro286Ser (c.856C>T) pathogenic?

RTN4IP1 p.Pro286Ser (c.856C>T) is classified Uncertain significance in RTN4IP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-06). AlphaMissense: likely benign (0.2031); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with RTN4IP1 p.Pro286Ser (c.856C>T)?

RTN4IP1 p.Pro286Ser (c.856C>T) is associated with Inborn genetic diseases (ClinVar).

How common is RTN4IP1 p.Pro286Ser (c.856C>T) in the general population?

RTN4IP1 p.Pro286Ser (c.856C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about RTN4IP1 p.Pro286Ser (c.856C>T)?

AlphaMissense predicts likely benign (score 0.2031) — an in-silico prediction, not a clinical call.

RTN4IP1 p.Pro286Ser

c.856C>T · VCV4157971

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2031 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2031	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -9.59	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 3.4	GERP 1.3, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 57 kb · p 0.005 · regional, not allelic
Overall
CADD	19.56	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 0.00167% Admixed American · 1/59,980 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000806% 13/1,613,698 alleles · very rare exomes 12/1,461,524 · genomes 1/152,174 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,980
European (non-Finnish)	0.00102%	98,328

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.Pro286Ser
Coding: c.856C>T
MANE Select: NM_032730
Type: single nucleotide variant
Location: chr6:106587813 (GRCh38)
Gene constraint: LOEUF 0.952 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.54 · 1 PDB
Residue 286: the enoyl reductase (er) domain; a UniProt-annotated variant site (in opa10); an α-helix

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 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
RTN4IP1 p.Asp133Glu Uncertain significance ★★ ⚠ same condition
RTN4IP1 p.Asp229Tyr 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-pro286ser (accessed [today's date]).

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