Is RIN2 p.Arg170Trp (c.508C>T) pathogenic?

RIN2 p.Arg170Trp (c.508C>T) is classified Uncertain significance in RIN2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-20). AlphaMissense: likely pathogenic (0.8128); Ultra-rare (popmax 0.0334%, afr); Associated with Inborn genetic diseases.

What condition is associated with RIN2 p.Arg170Trp (c.508C>T)?

RIN2 p.Arg170Trp (c.508C>T) is associated with Inborn genetic diseases (ClinVar).

How common is RIN2 p.Arg170Trp (c.508C>T) in the general population?

RIN2 p.Arg170Trp (c.508C>T) is ultra-rare (popmax 0.0334%, afr) (gnomAD).

What do computational predictors say about RIN2 p.Arg170Trp (c.508C>T)?

AlphaMissense predicts likely pathogenic (score 0.8128) — an in-silico prediction, not a clinical call.

RIN2 p.Arg170Trp

c.508C>T · rs377681843 · VCV1219021

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8128 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0334%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8128	likely pathogenic
REVEL	0.332	indeterminate
SaProt	LLR -14.40	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.39	acceptor loss · deltas
Pangolin	Δ0.21	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6.1	GERP 2.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 86 kb · p 0.14 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0334% African / African-American · 25/74,894 alleles

Filtering AF 0.0231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0198%

Overall 0.00409% 66/1,613,382 alleles · ultra-rare exomes 57/1,461,256 · genomes 9/152,126 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0334%	2,996
Admixed American	0.0117%	8,569
East Asian	0.00668%	14,966
European (non-Finnish)	0.00237%	42,135
Remaining individualsnot grpmax-eligible	0.0016%	62,462
Finnishnot grpmax-eligible	0.00157%	63,686
South Asian	0.0011%	91,080

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.Arg170Trp
Coding: c.508C>T
MANE Select: NM_018993
dbSNP: rs377681843
Type: single nucleotide variant
Location: chr20:19964996 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.30
Residue 170: the sh2 domain

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.Arg170= Uncertain significance ★ same residue
RIN2 p.Arg170Gln Uncertain significance ★ ⚠ 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.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-arg170trp (accessed [today's date]).

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