Is RIN2 p.Arg255Thr (c.764G>C) pathogenic?

RIN2 p.Arg255Thr (c.764G>C) is classified Uncertain significance in RIN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-31). AlphaMissense: likely pathogenic (0.9519); Ultra-rare (popmax 0.035%, amr); Associated with Inborn genetic diseases.

What condition is associated with RIN2 p.Arg255Thr (c.764G>C)?

RIN2 p.Arg255Thr (c.764G>C) is associated with Inborn genetic diseases (ClinVar).

How common is RIN2 p.Arg255Thr (c.764G>C) in the general population?

RIN2 p.Arg255Thr (c.764G>C) is ultra-rare (popmax 0.035%, amr) (gnomAD).

What do computational predictors say about RIN2 p.Arg255Thr (c.764G>C)?

AlphaMissense predicts likely pathogenic (score 0.9519) — an in-silico prediction, not a clinical call.

RIN2 p.Arg255Thr

c.764G>C · rs746529116 · VCV2161401

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9519 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.035%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9519	likely pathogenic
REVEL	0.275	benign-leaning
SaProt	LLR -6.01	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 86 kb · p 0.14 · regional, not allelic
Overall
CADD	28.4	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 0.035% Admixed American · 21/60,030 alleles

Filtering AF 0.0234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.0013% 21/1,614,008 alleles · ultra-rare exomes 21/1,461,708 · genomes 0/152,300 · joint denominator

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.Arg255Thr
Coding: c.764G>C
MANE Select: NM_018993
dbSNP: rs746529116
Type: single nucleotide variant
Location: chr20:19974789 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.30

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.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.Arg290Leu Uncertain significance ★★ ⚠ same condition
RIN2 p.Arg303Gln Uncertain significance ★★ ⚠ same condition
RIN2 p.Arg446Gln Uncertain significance ★★ ⚠ same condition
RIN2 p.Arg516Gly 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-arg255thr (accessed [today's date]).

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