Is RIN2 p.Val840Ile (c.2518G>A) pathogenic?

RIN2 p.Val840Ile (c.2518G>A) is classified Uncertain significance in RIN2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-19). AlphaMissense: likely benign (0.0756); Ultra-rare (popmax 0.0383%, amr); Associated with RIN2 syndrome.

What condition is associated with RIN2 p.Val840Ile (c.2518G>A)?

RIN2 p.Val840Ile (c.2518G>A) is associated with RIN2 syndrome (ClinVar).

How common is RIN2 p.Val840Ile (c.2518G>A) in the general population?

RIN2 p.Val840Ile (c.2518G>A) is ultra-rare (popmax 0.0383%, amr) (gnomAD).

What do computational predictors say about RIN2 p.Val840Ile (c.2518G>A)?

AlphaMissense predicts likely benign (score 0.0756) — an in-silico prediction, not a clinical call.

RIN2 p.Val840Ile

c.2518G>A · rs188424417 · VCV1348826

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0756 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0383%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RIN2 syndrome

Computational evidence

Protein change
AlphaMissense	0.0756	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -6.15	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 6.8	GERP 7.2, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 4,195 bp · p 0.15 · regional, not allelic
Overall
CADD	17.28	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 0.0383% Admixed American · 23/60,010 alleles

Filtering AF 0.0261% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.0117% 189/1,613,922 alleles · ultra-rare exomes 171/1,461,708 · genomes 18/152,214 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0383%	2,609
European (non-Finnish)	0.0127%	7,866
African / African-American	0.00933%	10,714
East Asian	0.00446%	22,444
South Asian	0.00439%	22,770
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
Remaining individualsnot grpmax-eligible	0.0032%	31,243

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.Val840Ile
Coding: c.2518G>A
MANE Select: NM_018993
dbSNP: rs188424417
Type: single nucleotide variant
Location: chr20:20000766 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.30
Residue 840: the ras-associating domain

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

Disease context

RIN2 syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RIN2 p.Asn266Ile Uncertain significance ★★ ⚠ same condition
RIN2 p.His340Arg Uncertain significance ★★ ⚠ same condition
RIN2 p.Pro308Ala Uncertain significance ★★ ⚠ same condition
RIN2 p.Pro308Gln Uncertain significance ★★ ⚠ same condition
RIN2 p.Ser800Cys Uncertain significance ★★ ⚠ same condition
RIN2 c.159-17G>A Likely benign ★★ same condition
RIN2 c.2201-47G>A Benign ★★ same condition
RIN2 p.Ala617= Benign/Likely benign ★★ 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-val840ile (accessed [today's date]).

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