Is RIN2 p.Phe504Leu (c.1512C>A) pathogenic?

RIN2 p.Phe504Leu (c.1512C>A) is classified Uncertain significance in RIN2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-31). AlphaMissense: likely pathogenic (0.825); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with RIN2 p.Phe504Leu (c.1512C>A)?

RIN2 p.Phe504Leu (c.1512C>A) is associated with Inborn genetic diseases (ClinVar).

How common is RIN2 p.Phe504Leu (c.1512C>A) in the general population?

RIN2 p.Phe504Leu (c.1512C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RIN2 p.Phe504Leu (c.1512C>A)?

AlphaMissense predicts likely pathogenic (score 0.825) — an in-silico prediction, not a clinical call.

RIN2 p.Phe504Leu

c.1512C>A · rs2515517024 · VCV2531820

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.825 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.825	likely pathogenic
REVEL	0.168	moderately benign-leaning
SaProt	LLR -7.67	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 3.3	GERP 4.9, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 86 kb · p 0.14 · regional, not allelic
Overall
CADD	20.3	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.Phe504Leu
Coding: c.1512C>A
MANE Select: NM_018993
dbSNP: rs2515517024
Type: single nucleotide variant
Location: chr20:19975537 (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-phe504leu (accessed [today's date]).

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