Is RIN2 p.Arg446Gln (c.1337G>A) pathogenic?

RIN2 p.Arg446Gln (c.1337G>A) is classified Uncertain significance in RIN2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-05-04). AlphaMissense: likely benign (0.0792); Very rare (popmax 0.00446%, eas); Associated with Inborn genetic diseases.

What condition is associated with RIN2 p.Arg446Gln (c.1337G>A)?

RIN2 p.Arg446Gln (c.1337G>A) is associated with Inborn genetic diseases (ClinVar).

How common is RIN2 p.Arg446Gln (c.1337G>A) in the general population?

RIN2 p.Arg446Gln (c.1337G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about RIN2 p.Arg446Gln (c.1337G>A)?

AlphaMissense predicts likely benign (score 0.0792) — an in-silico prediction, not a clinical call.

RIN2 p.Arg446Gln

c.1337G>A · rs1172506359 · VCV436536

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0792 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0792	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -6.36	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 5.2	GERP 2.2, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 86 kb · p 0.14 · regional, not allelic
Overall
CADD	23.5	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 0.00446% East Asian · 2/44,870 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.00031% 5/1,613,722 alleles · very rare exomes 5/1,461,370 · genomes 0/152,352 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,435
South Asian	0.0022%	45,520
European (non-Finnish)	8.48e-05%	1,179,754

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.Arg446Gln
Coding: c.1337G>A
MANE Select: NM_018993
dbSNP: rs1172506359
Type: single nucleotide variant
Location: chr20:19975362 (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.Arg446= Benign/Likely 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-arg446gln (accessed [today's date]).

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