Is RIN2 p.Ala519Pro (c.1555G>C) pathogenic?

RIN2 p.Ala519Pro (c.1555G>C) is classified Uncertain significance in RIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-16). AlphaMissense: likely pathogenic (0.9446); Absent from gnomAD v4.1; Associated with RIN2 syndrome.

What condition is associated with RIN2 p.Ala519Pro (c.1555G>C)?

RIN2 p.Ala519Pro (c.1555G>C) is associated with RIN2 syndrome (ClinVar).

How common is RIN2 p.Ala519Pro (c.1555G>C) in the general population?

RIN2 p.Ala519Pro (c.1555G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RIN2 p.Ala519Pro (c.1555G>C)?

AlphaMissense predicts likely pathogenic (score 0.9446) — an in-silico prediction, not a clinical call.

RIN2 p.Ala519Pro

c.1555G>C · rs2515517681 · VCV2435435

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9446 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RIN2 syndrome

Computational evidence

Protein change
AlphaMissense	0.9446	likely pathogenic
REVEL	0.219	benign-leaning
SaProt	LLR -9.79	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 6.7, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 101 bp · p 0.075 · regional, not allelic
Overall
CADD	24.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RIN2
Protein: p.Ala519Pro
Coding: c.1555G>C
MANE Select: NM_018993
dbSNP: rs2515517681
Type: single nucleotide variant
Location: chr20:19975580 (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

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

Similar variants

RIN2 p.Ala519= Benign ★ same residue
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 p.Val840Ile Uncertain significance ★★ ⚠ same condition
RIN2 c.159-17G>A 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-ala519pro (accessed [today's date]).

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