Is RIN2 p.Pro476Arg (c.1427C>G) pathogenic?

RIN2 p.Pro476Arg (c.1427C>G) is classified Conflicting classifications of pathogenicity in RIN2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-22). AlphaMissense: likely benign (0.2649); Rare (popmax 0.51%, afr).

How common is RIN2 p.Pro476Arg (c.1427C>G) in the general population?

RIN2 p.Pro476Arg (c.1427C>G) is rare (popmax 0.51%, afr) (gnomAD).

What do computational predictors say about RIN2 p.Pro476Arg (c.1427C>G)?

AlphaMissense predicts likely benign (score 0.2649) — an in-silico prediction, not a clinical call.

RIN2 p.Pro476Arg

c.1427C>G · rs35142632 · VCV212054

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2649 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.51%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2649	likely benign
REVEL	0.12	moderately benign-leaning
SaProt	LLR -6.88	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 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 86 kb · p 0.14 · regional, not allelic
Overall
CADD	24.8	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 0.51% African / African-American · 383/75,072 alleles

Filtering AF 0.468% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.451%

Overall 0.0252% 406/1,614,078 alleles · rare exomes 181/1,461,710 · genomes 225/152,368 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.51%	196
Remaining individualsnot grpmax-eligible	0.0224%	4,463
Admixed American	0.0133%	7,503
European (non-Finnish)	8.48e-05%	1,179,903

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.Pro476Arg
Coding: c.1427C>G
MANE Select: NM_018993
dbSNP: rs35142632
Type: single nucleotide variant
Location: chr20:19975452 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.30
Residue 476: the 'disordered' region

Full RIN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RIN2 p.Pro476Ala Uncertain significance ★ ⚠ same residue
RIN2 p.Pro476Leu Uncertain significance ★ ⚠ same residue
RIN2 p.Ala205Val Uncertain significance ★★ ⚠ same type
RIN2 p.Ala72Thr Uncertain significance ★★ ⚠ same type
RIN2 p.Ala8Thr Uncertain significance ★★ ⚠ same type
RIN2 p.Arg135Cys Uncertain significance ★★ ⚠ same type
RIN2 p.Arg170Trp Uncertain significance ★★ ⚠ same type
RIN2 p.Arg255Thr Uncertain significance ★★ ⚠ 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/rin2-p-pro476arg (accessed [today's date]).

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