Is RIN2 p.Arg135His (c.404G>A) pathogenic?

RIN2 p.Arg135His (c.404G>A) is classified Conflicting classifications of pathogenicity in RIN2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-05-11). AlphaMissense: likely benign (0.1467); Ultra-rare (popmax 0.0552%, sas); Associated with Inborn genetic diseases.

What condition is associated with RIN2 p.Arg135His (c.404G>A)?

RIN2 p.Arg135His (c.404G>A) is associated with Inborn genetic diseases, RIN2 syndrome (ClinVar).

How common is RIN2 p.Arg135His (c.404G>A) in the general population?

RIN2 p.Arg135His (c.404G>A) is ultra-rare (popmax 0.0552%, sas) (gnomAD).

What do computational predictors say about RIN2 p.Arg135His (c.404G>A)?

AlphaMissense predicts likely benign (score 0.1467) — an in-silico prediction, not a clinical call.

RIN2 p.Arg135His

c.404G>A · rs200460217 · VCV1203399

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1467 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0552%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1467	likely benign
REVEL	0.401	indeterminate
SaProt	LLR -10.29	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 86 kb · p 0.14 · regional, not allelic
Overall
CADD	32.0	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 0.0552% South Asian · 49/88,688 alleles

Filtering AF 0.0429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0385%

Overall 0.00991% 159/1,605,088 alleles · ultra-rare exomes 146/1,453,038 · genomes 13/152,050 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0552%	1,810
European (non-Finnish)	0.0085%	11,760
Admixed American	0.0068%	14,707
African / African-American	0.00401%	24,925
Ashkenazi Jewishnot grpmax-eligible	0.00341%	29,364
Remaining individualsnot grpmax-eligible	0.00321%	31,105

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.Arg135His
Coding: c.404G>A
MANE Select: NM_018993
dbSNP: rs200460217
Type: single nucleotide variant
Location: chr20:19960752 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.30
Residue 135: 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

Also linked: RIN2 syndrome

Similar variants

RIN2 p.Arg135Cys Uncertain significance ★★ ⚠ same residue
RIN2 p.Ala205Val Uncertain significance ★★ ⚠ same condition
RIN2 p.Ala72Thr 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-arg135his (accessed [today's date]).

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