Is RIN2 p.Pro308Leu (c.923C>T) pathogenic?

RIN2 p.Pro308Leu (c.923C>T) is classified Uncertain significance in RIN2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-17). AlphaMissense: ambiguous (0.4475); Ultra-rare (popmax 0.0143%, sas); Associated with Inborn genetic diseases.

What condition is associated with RIN2 p.Pro308Leu (c.923C>T)?

RIN2 p.Pro308Leu (c.923C>T) is associated with Inborn genetic diseases (ClinVar).

How common is RIN2 p.Pro308Leu (c.923C>T) in the general population?

RIN2 p.Pro308Leu (c.923C>T) is ultra-rare (popmax 0.0143%, sas) (gnomAD).

What do computational predictors say about RIN2 p.Pro308Leu (c.923C>T)?

AlphaMissense predicts ambiguous (score 0.4475) — an in-silico prediction, not a clinical call.

RIN2 p.Pro308Leu

c.923C>T · rs374058245 · VCV1309549

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4475 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0143%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4475	ambiguous
REVEL	0.19	benign-leaning
SaProt	LLR -10.77	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2.2, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 86 kb · p 0.14 · regional, not allelic
Overall
CADD	26.7	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 0.0143% South Asian · 13/90,894 alleles

Filtering AF 0.00846% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00662%

Overall 0.00567% 91/1,603,548 alleles · ultra-rare exomes 79/1,452,176 · genomes 12/151,372 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0143%	6,992
Remaining individualsnot grpmax-eligible	0.00644%	15,531
European (non-Finnish)	0.00581%	17,225
African / African-American	0.00537%	18,616
East Asian	0.00223%	44,760
Admixed American	0.00167%	59,894

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.Pro308Leu
Coding: c.923C>T
MANE Select: NM_018993
dbSNP: rs374058245
Type: single nucleotide variant
Location: chr20:19974948 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.30
Residue 308: the 'disordered' region

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.Pro308Ala Uncertain significance ★★ ⚠ same residue
RIN2 p.Pro308Arg Uncertain significance ★★ ⚠ same residue
RIN2 p.Pro308Gln Uncertain significance ★★ ⚠ same residue
RIN2 p.Pro308= Likely benign ★★ 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

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-pro308leu (accessed [today's date]).

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