Is RIN1 p.Arg99Cys (c.295C>T) pathogenic?

RIN1 p.Arg99Cys (c.295C>T) is classified Uncertain significance in RIN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-06). AlphaMissense: likely benign (0.1047); Very rare (popmax 0.00175%, amr).

How common is RIN1 p.Arg99Cys (c.295C>T) in the general population?

RIN1 p.Arg99Cys (c.295C>T) is very rare (popmax 0.00175%, amr) (gnomAD).

What do computational predictors say about RIN1 p.Arg99Cys (c.295C>T)?

AlphaMissense predicts likely benign (score 0.1047) — an in-silico prediction, not a clinical call.

RIN1 p.Arg99Cys

c.295C>T · rs576392806 · VCV2355128

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1047 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00175%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1047	likely benign
REVEL	0.118	moderately benign-leaning
SaProt	LLR -10.54	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 1.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 4,123 bp · p 0.45 · regional, not allelic
Overall
CADD	24.4	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

Grpmax group 0.00175% Admixed American · 1/57,060 alleles

Filtering AF 0.000126% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000504% 8/1,587,214 alleles · very rare exomes 5/1,435,008 · genomes 3/152,206 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00175%	57,060
Remaining individualsnot grpmax-eligible	0.00164%	61,162
Finnishnot grpmax-eligible	0.00159%	63,014
European (non-Finnish)	0.000429%	233,083

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: RIN1
Protein: p.Arg99Cys
Coding: c.295C>T
MANE Select: NM_004292
dbSNP: rs576392806
Type: single nucleotide variant
Location: chr11:66335849 (GRCh38)
Gene constraint: LOEUF 1.22 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.78
Residue 99: the sh2 domain

Full RIN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RIN1 p.Arg99His Uncertain significance ★ ⚠ same residue
RIN1 p.Ala690= Benign ★★ same type
RIN1 p.Gly737= Benign ★★ same type
RIN1 p.Thr643= Benign/Likely benign ★★ same type
RIN1 p.Val700Ile Benign ★★ same type
RIN1 p.Ala111Thr Uncertain significance ★ ⚠ same type
RIN1 p.Ala168Thr Uncertain significance ★ ⚠ same type
RIN1 p.Ala221Ser 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/rin1-p-arg99cys (accessed [today's date]).

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