Is RIN2 p.Arg14Ter (c.40C>T) pathogenic?

RIN2 p.Arg14Ter (c.40C>T) is classified Conflicting classifications of pathogenicity in RIN2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-06). Very rare (popmax 0.00835%, afr); Associated with RIN2-related disorder.

What condition is associated with RIN2 p.Arg14Ter (c.40C>T)?

RIN2 p.Arg14Ter (c.40C>T) is associated with RIN2-related disorder (ClinVar).

How common is RIN2 p.Arg14Ter (c.40C>T) in the general population?

RIN2 p.Arg14Ter (c.40C>T) is very rare (popmax 0.00835%, afr) (gnomAD).

RIN2 p.Arg14Ter

c.40C>T · rs777979761 · VCV2140100

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00835%, afr)

Conditions

RIN2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 13
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.8, phastCons 1
Overall
CADD	44.0	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 0.00835% African / African-American · 6/71,852 alleles

Filtering AF 0.00359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00246%

Overall 0.00197% 30/1,523,986 alleles · very rare exomes 26/1,371,876 · genomes 4/152,110 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00835%	11,975
Admixed American	0.00212%	47,064
European (non-Finnish)	0.00203%	49,247

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.Arg14Ter
Coding: c.40C>T
MANE Select: NM_018993
dbSNP: rs777979761
Type: single nucleotide variant
Location: chr20:19889641 (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

RIN2-related disorder

Similar variants

RIN2 p.Arg14Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
RIN2 p.Arg14= Likely benign ★ same residue
RIN2 c.351+2T>A Likely pathogenic same condition
RIN2 p.Asn341Ser Uncertain significance ⚠ same condition
RIN2 c.-36-2899G>A Likely benign same condition
RIN2 p.Ala315= Likely benign same condition
RIN2 p.Arg632= Likely benign same condition
RIN2 p.His250= Likely benign 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-arg14ter (accessed [today's date]).

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