Is RIN2 p.Arg428Trp (c.1282C>T) pathogenic?

RIN2 p.Arg428Trp (c.1282C>T) is classified Uncertain significance in RIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-14). AlphaMissense: ambiguous (0.5416); Ultra-rare (popmax 0.0224%, eas); Associated with Inborn genetic diseases.

What condition is associated with RIN2 p.Arg428Trp (c.1282C>T)?

RIN2 p.Arg428Trp (c.1282C>T) is associated with Inborn genetic diseases (ClinVar).

How common is RIN2 p.Arg428Trp (c.1282C>T) in the general population?

RIN2 p.Arg428Trp (c.1282C>T) is ultra-rare (popmax 0.0224%, eas) (gnomAD).

What do computational predictors say about RIN2 p.Arg428Trp (c.1282C>T)?

AlphaMissense predicts ambiguous (score 0.5416) — an in-silico prediction, not a clinical call.

RIN2 p.Arg428Trp

c.1282C>T · VCV3789170

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5416 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0224%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5416	ambiguous
REVEL	0.232	benign-leaning
SaProt	LLR -10.21	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP -0.16, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 86 kb · p 0.14 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0224% East Asian · 10/44,582 alleles

Filtering AF 0.0121% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00922%

Overall 0.000747% 12/1,606,112 alleles · ultra-rare exomes 10/1,453,882 · genomes 2/152,230 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0224%	4,458
European (non-Finnish)	0.00017%	588,308

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: RIN2
Protein: p.Arg428Trp
Coding: c.1282C>T
MANE Select: NM_018993
Type: single nucleotide variant
Location: chr20:19975307 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.30
Residue 428: the 'disordered' region

Full RIN2 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

RIN2 p.Arg428Leu Uncertain significance ★ ⚠ same residue
RIN2 p.Arg428= Likely benign ★ same residue
RIN2 p.Ala205Val Uncertain significance ★★ ⚠ same condition
RIN2 p.Ala72Thr Uncertain significance ★★ ⚠ same condition
RIN2 p.Arg135Cys Uncertain significance ★★ ⚠ same condition
RIN2 p.Arg170Trp Uncertain significance ★★ ⚠ same condition
RIN2 p.Arg255Thr Uncertain significance ★★ ⚠ same condition
RIN2 p.Arg290Leu 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/rin2-p-arg428trp (accessed [today's date]).

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