Is INS p.Arg89Pro (c.266G>C) pathogenic?

INS p.Arg89Pro (c.266G>C) is classified Pathogenic in INS (ClinVar, No assertion criteria, 1 submitter; last evaluated 1997-05-01). AlphaMissense: likely pathogenic (0.8607); Very rare (popmax 0.000425%, nfe); Associated with hyperproinsulinemia.

What condition is associated with INS p.Arg89Pro (c.266G>C)?

INS p.Arg89Pro (c.266G>C) is associated with hyperproinsulinemia (ClinVar).

How common is INS p.Arg89Pro (c.266G>C) in the general population?

INS p.Arg89Pro (c.266G>C) is very rare (popmax 0.000425%, nfe) (gnomAD).

What do computational predictors say about INS p.Arg89Pro (c.266G>C)?

AlphaMissense predicts likely pathogenic (score 0.8607) — an in-silico prediction, not a clinical call.

INS p.Arg89Pro

c.266G>C · rs28933985 · VCV13383

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8607 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000425%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperproinsulinemia

Computational evidence

Protein change
AlphaMissense	0.8607	likely pathogenic ✓ concordant with ClinVar
REVEL	0.734	pathogenic-leaning
SaProt	LLR -10.70	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.1	GERP -0.15, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 1,060 bp · p 0.36 · regional, not allelic
Overall
CADD	24.8	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 0.000425% European (non-Finnish) · 5/1,176,380 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000312% 5/1,603,810 alleles · very rare exomes 5/1,451,498 · genomes 0/152,312 · joint denominator

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.Arg89Pro
Coding: c.266G>C
MANE Select: NM_000207
dbSNP: rs28933985
Type: single nucleotide variant
Location: chr11:2159919 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 53.19 · 386 PDB
Residue 89: a UniProt-annotated variant site (in pndm4); a UniProt-annotated variant site (in hpri; impairs post-translational cleavage); a UniProt-annotated variant site (in hpri; kyoto)

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

Disease context

hyperproinsulinemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

INS p.Arg89His Pathogenic/Likely pathogenic ★★ same residue
INS p.Arg89Leu Pathogenic same residue
INS p.Arg89Cys Pathogenic/Likely pathogenic ★★ same residue
INS c.-152C>A Pathogenic/Likely pathogenic ★★ same condition
INS c.-152C>G Pathogenic ★★ same condition
INS p.Met1Val Pathogenic/Likely pathogenic ★★ same condition
INS c.187+3G>A Uncertain significance ★★ same condition
INS c.-152C>T 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/ins-p-arg89pro (accessed [today's date]).

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