Is RIN2 p.Lys491Arg (c.1472A>G) pathogenic?

RIN2 p.Lys491Arg (c.1472A>G) is classified Uncertain significance in RIN2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-06). AlphaMissense: likely benign (0.065); Ultra-rare (popmax 0.0657%, mid); Associated with Inborn genetic diseases.

What condition is associated with RIN2 p.Lys491Arg (c.1472A>G)?

RIN2 p.Lys491Arg (c.1472A>G) is associated with Inborn genetic diseases (ClinVar).

How common is RIN2 p.Lys491Arg (c.1472A>G) in the general population?

RIN2 p.Lys491Arg (c.1472A>G) is ultra-rare (popmax 0.0657%, mid) (gnomAD).

What do computational predictors say about RIN2 p.Lys491Arg (c.1472A>G)?

AlphaMissense predicts likely benign (score 0.065) — an in-silico prediction, not a clinical call.

RIN2 p.Lys491Arg

c.1472A>G · rs773174079 · VCV430462

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.065 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0657%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.065	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -7.13	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.2	GERP 1.4, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 86 kb · p 0.14 · regional, not allelic
Overall
CADD	17.07	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 0.0657% Middle Eastern · 4/6,084 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.0057% 92/1,613,936 alleles · ultra-rare exomes 90/1,461,712 · genomes 2/152,224 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0657%	1,521
Remaining individualsnot grpmax-eligible	0.0144%	6,941
South Asian	0.0143%	7,007
European (non-Finnish)	0.00559%	17,877

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.Lys491Arg
Coding: c.1472A>G
MANE Select: NM_018993
dbSNP: rs773174079
Type: single nucleotide variant
Location: chr20:19975497 (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.Arg255Thr 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

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-lys491arg (accessed [today's date]).

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