Is RIN2 p.Arg676Trp (c.2026C>T) pathogenic?

RIN2 p.Arg676Trp (c.2026C>T) is classified Uncertain significance in RIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-12). AlphaMissense: likely pathogenic (0.658); Very rare (popmax 0.00446%, eas); Associated with Inborn genetic diseases.

What condition is associated with RIN2 p.Arg676Trp (c.2026C>T)?

RIN2 p.Arg676Trp (c.2026C>T) is associated with Inborn genetic diseases (ClinVar).

How common is RIN2 p.Arg676Trp (c.2026C>T) in the general population?

RIN2 p.Arg676Trp (c.2026C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about RIN2 p.Arg676Trp (c.2026C>T)?

AlphaMissense predicts likely pathogenic (score 0.658) — an in-silico prediction, not a clinical call.

RIN2 p.Arg676Trp

c.2026C>T · VCV3314383

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.658 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.658	likely pathogenic
REVEL	0.366	indeterminate
SaProt	LLR -11.21	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.5	GERP 2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 241 bp · p 0.45 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00446% East Asian · 2/44,892 alleles

Filtering AF 0.000877% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000558% 9/1,613,552 alleles · very rare exomes 8/1,461,326 · genomes 1/152,226 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,446
South Asian	0.0033%	30,303
Remaining individualsnot grpmax-eligible	0.0016%	62,460
European (non-Finnish)	0.000254%	393,269

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.Arg676Trp
Coding: c.2026C>T
MANE Select: NM_018993
Type: single nucleotide variant
Location: chr20:19990269 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.30
Residue 676: the vps9 domain

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.Arg676Gln 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
RIN2 p.Arg303Gln 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-arg676trp (accessed [today's date]).

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