Is RIN2 p.Val656Ile (c.1966G>A) pathogenic?

RIN2 p.Val656Ile (c.1966G>A) is classified Likely benign in RIN2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-23). AlphaMissense: likely benign (0.0769); Rare (popmax 0.502%, sas).

How common is RIN2 p.Val656Ile (c.1966G>A) in the general population?

RIN2 p.Val656Ile (c.1966G>A) is rare (popmax 0.502%, sas) (gnomAD).

What do computational predictors say about RIN2 p.Val656Ile (c.1966G>A)?

AlphaMissense predicts likely benign (score 0.0769) — an in-silico prediction, not a clinical call.

RIN2 p.Val656Ile

c.1966G>A · rs201964534 · VCV425266

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0769 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.502%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0769	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -6.72	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 5	GERP 4.5, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 241 bp · p 0.45 · regional, not allelic
Overall
CADD	16.42	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 0.502% South Asian · 453/90,304 alleles

Filtering AF 0.463% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.448%

Overall 0.148% 2,378/1,611,814 alleles · rare exomes 2,262/1,459,446 · genomes 116/152,368 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.502%	199
European (non-Finnish)	0.152%	658
Remaining individualsnot grpmax-eligible	0.136%	735
Middle Eastern	0.116%	865
Admixed American	0.0419%	2,389
African / African-American	0.012%	8,339
Finnishnot grpmax-eligible	0.00939%	10,650
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,474

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.Val656Ile
Coding: c.1966G>A
MANE Select: NM_018993
dbSNP: rs201964534
Type: single nucleotide variant
Location: chr20:19990209 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.30
Residue 656: the vps9 domain

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

Similar variants

RIN2 p.Val656Gly 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
RIN2 p.Arg290Leu 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-val656ile (accessed [today's date]).

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