Is RIN2 p.Thr23Arg (c.68C>G) pathogenic?

RIN2 p.Thr23Arg (c.68C>G) is classified Uncertain significance in RIN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-10). AlphaMissense: ambiguous (0.3523); Ultra-rare (popmax 0.0718%, sas); Associated with Inborn genetic diseases.

What condition is associated with RIN2 p.Thr23Arg (c.68C>G)?

RIN2 p.Thr23Arg (c.68C>G) is associated with Inborn genetic diseases (ClinVar).

How common is RIN2 p.Thr23Arg (c.68C>G) in the general population?

RIN2 p.Thr23Arg (c.68C>G) is ultra-rare (popmax 0.0718%, sas) (gnomAD).

What do computational predictors say about RIN2 p.Thr23Arg (c.68C>G)?

AlphaMissense predicts ambiguous (score 0.3523) — an in-silico prediction, not a clinical call.

RIN2 p.Thr23Arg

c.68C>G · rs749789238 · VCV2414546

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3523 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0718%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3523	ambiguous
REVEL	0.25	benign-leaning
SaProt	LLR -6.32	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 7.6	GERP 2.2, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 86 kb · p 0.14 · regional, not allelic
Overall
CADD	27.0	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 0.0718% South Asian · 63/87,700 alleles

Filtering AF 0.0576% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0524%

Overall 0.0042% 67/1,596,276 alleles · ultra-rare exomes 67/1,443,964 · genomes 0/152,312 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0718%	1,392
Remaining individualsnot grpmax-eligible	0.00646%	15,489

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.Thr23Arg
Coding: c.68C>G
MANE Select: NM_018993
dbSNP: rs749789238
Type: single nucleotide variant
Location: chr20:19935109 (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.Thr23Ala 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.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

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-thr23arg (accessed [today's date]).

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