Is RIN2 p.Ser306fs (c.916_917insGC) pathogenic?

RIN2 p.Ser306fs (c.916917insGC) is classified Uncertain significance in RIN2 (ClinVar, Single submitter, 2 submitters). Low-frequency (popmax 1.9%, nfe).

How common is RIN2 p.Ser306fs (c.916_917insGC) in the general population?

RIN2 p.Ser306fs (c.916_917insGC) is low-frequency (popmax 1.9%, nfe) (gnomAD).

RIN2 p.Ser306fs

c.916_917insGC · rs1568686983 · VCV591323

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

low-frequency (popmax 1.9%, nfe)

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 1.9% European (non-Finnish) · 21,034/1,109,884 alleles

Filtering AF 1.87% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.86%

Overall 1.5% 23,026/1,533,964 alleles · low-frequency exomes 22,996/1,384,666 · genomes 30/149,298 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.9%	53
Remaining individualsnot grpmax-eligible	1.25%	80
Middle Eastern	0.697%	143
African / African-American	0.587%	170
South Asian	0.545%	184
Ashkenazi Jewishnot grpmax-eligible	0.485%	206
East Asian	0.242%	413
Admixed American	0.0541%	1,849
Finnishnot grpmax-eligible	0.0174%	5,741

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.Ser306fs
Coding: c.916_917insGC
MANE Select: NM_018993
dbSNP: rs1568686983
Type: Insertion
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 306: the 'disordered' region

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

Similar variants

RIN2 p.Ser306= Likely benign ★ same residue
RIN2 p.Pro308fs Pathogenic ★ 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-ser306fs (accessed [today's date]).

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