Is INS p.Arg46Ter (c.136C>T) pathogenic?

INS p.Arg46Ter (c.136C>T) is classified Likely pathogenic in INS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-13). Very rare (popmax 8.48e-05%, nfe); Associated with INS-related disorder.

What condition is associated with INS p.Arg46Ter (c.136C>T)?

INS p.Arg46Ter (c.136C>T) is associated with INS-related disorder (ClinVar).

How common is INS p.Arg46Ter (c.136C>T) in the general population?

INS p.Arg46Ter (c.136C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

INS p.Arg46Ter

c.136C>T · rs1225892123 · VCV2630345

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

INS-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 2 of 3
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP -0.05, phastCons 0.98
Overall
CADD	36.0	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 8.48e-05% European (non-Finnish) · 1/1,179,804 alleles

Overall 0.000137% 2/1,460,366 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,470
European (non-Finnish)grpmax	8.48e-05%	1,179,805

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: INS
Protein: p.Arg46Ter
Coding: c.136C>T
MANE Select: NM_000207
dbSNP: rs1225892123
Type: single nucleotide variant
Location: chr11:2160836 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 53.19 · 386 PDB
Residue 46: a UniProt-annotated variant site (in mody10; reduces binding affinity to insr; reduces biological activity; reduces folding properties); an α-helix

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

Disease context

INS-related disorder

Similar variants

INS p.Arg46Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
INS p.Arg89Cys Pathogenic/Likely pathogenic ★★ same condition
INS p.Arg89His Pathogenic/Likely pathogenic ★★ same condition
INS p.Gly32Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
INS p.Gly69Asp Uncertain significance ★★ ⚠ same condition
INS p.Pro9Ser Uncertain significance ★★ ⚠ same condition
INS p.Ala24= Benign/Likely benign ★★ same condition
INS p.Cys95Tyr Likely pathogenic ★ ⚠ 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/ins-p-arg46ter (accessed [today's date]).

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