Is RIN2 p.Pro309fs (c.923dup) pathogenic?

RIN2 p.Pro309fs (c.923dup) is classified Uncertain significance in RIN2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2018-09-16). Rare (popmax 0.498%, amr).

How common is RIN2 p.Pro309fs (c.923dup) in the general population?

RIN2 p.Pro309fs (c.923dup) is rare (popmax 0.498%, amr) (gnomAD).

RIN2 p.Pro309fs

c.923dup · rs1568687023 · VCV591062

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.498%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 9 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5	GERP 2.2, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.498% Admixed American · 292/58,662 alleles

Filtering AF 0.451% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.432%

Overall 0.0643% 1,009/1,569,076 alleles · rare exomes 949/1,419,914 · genomes 60/149,162 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.498%	201
Amishnot grpmax-eligible	0.112%	896
African / African-American	0.109%	914
Remaining individualsnot grpmax-eligible	0.102%	982
Ashkenazi Jewishnot grpmax-eligible	0.0925%	1,081
Middle Eastern	0.0839%	1,192
European (non-Finnish)	0.0439%	2,276
South Asian	0.0244%	4,096
Finnishnot grpmax-eligible	0.0237%	4,211
East Asian	0.00677%	14,773

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.Pro309fs
Coding: c.923dup
MANE Select: NM_018993
dbSNP: rs1568687023
Type: Duplication
Location: chr20:19974941 (GRCh38)
Gene constraint: LOEUF 0.637 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.30
Residue 309: the 'disordered' region

Full RIN2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RIN2 p.Pro309Ala Uncertain significance ★ ⚠ same residue
RIN2 p.Leu702fs Likely pathogenic ★ same type
RIN2 p.Val641fs Pathogenic ★ same type
RIN2 p.Pro225_Pro226insAsnLeuProPro Uncertain significance ★ same type
RIN2 c.464-270dup Likely benign ★ same type
RIN2 c.628+268dup Benign ★ same type
RIN2 c.-36-267_-36-265dup Likely benign ★ same type
RIN2 c.-36-2935dup Benign ★ 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/rin2-p-pro309fs (accessed [today's date]).

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