Is RIN1 p.Ser112Arg (c.336T>G) pathogenic?

RIN1 p.Ser112Arg (c.336T>G) is classified Uncertain significance in RIN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-13). AlphaMissense: ambiguous (0.4253); Ultra-rare (popmax 0.0446%, eas).

How common is RIN1 p.Ser112Arg (c.336T>G) in the general population?

RIN1 p.Ser112Arg (c.336T>G) is ultra-rare (popmax 0.0446%, eas) (gnomAD).

What do computational predictors say about RIN1 p.Ser112Arg (c.336T>G)?

AlphaMissense predicts ambiguous (score 0.4253) — an in-silico prediction, not a clinical call.

RIN1 p.Ser112Arg

c.336T>G · rs567439359 · VCV2400476

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4253 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0446%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4253	ambiguous
REVEL	0.165	moderately benign-leaning
SaProt	LLR -8.29	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.3	GERP -2.8
Regional constraint	o/e 0.98	unconstrained · MANE · 4,123 bp · p 0.45 · regional, not allelic
Overall
CADD	0.285	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 0.0446% East Asian · 20/44,818 alleles

Filtering AF 0.0295% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0246%

Overall 0.00143% 23/1,610,180 alleles · ultra-rare exomes 19/1,457,880 · genomes 4/152,300 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0446%	2,241
Middle Eastern	0.0166%	6,036
Remaining individualsnot grpmax-eligible	0.00321%	31,154

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.Ser112Arg
Coding: c.336T>G
MANE Select: NM_004292
dbSNP: rs567439359
Type: single nucleotide variant
Location: chr11:66335808 (GRCh38)
Gene constraint: LOEUF 1.22 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.78
Residue 112: the sh2 domain

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

Similar variants

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
RIN1 p.Ala31Val 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-ser112arg (accessed [today's date]).

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