Is RIN2 p.Asp445Gly (c.1334A>G) pathogenic?

RIN2 p.Asp445Gly (c.1334A>G) is classified Uncertain significance in RIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-02). AlphaMissense: likely benign (0.1214); Very rare (popmax 0.00133%, afr).

How common is RIN2 p.Asp445Gly (c.1334A>G) in the general population?

RIN2 p.Asp445Gly (c.1334A>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about RIN2 p.Asp445Gly (c.1334A>G)?

AlphaMissense predicts likely benign (score 0.1214) — an in-silico prediction, not a clinical call.

RIN2 p.Asp445Gly

c.1334A>G · rs1337320171 · VCV1304707

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1214 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1214	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -7.02	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 11	GERP 2.2, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 86 kb · p 0.14 · regional, not allelic
Overall
CADD	24.3	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 0.00133% African / African-American · 1/74,934 alleles

Overall 0.000124% 2/1,613,614 alleles · very rare exomes 1/1,461,362 · genomes 1/152,252 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,934
European (non-Finnish)	8.48e-05%	1,179,759

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.Asp445Gly
Coding: c.1334A>G
MANE Select: NM_018993
dbSNP: rs1337320171
Type: single nucleotide variant
Location: chr20:19975359 (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

Similar variants

RIN2 p.Asp445Asn Uncertain significance ★★ ⚠ same residue
RIN2 p.Asp445= Likely benign ★ 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

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-asp445gly (accessed [today's date]).

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