Is INS p.Thr97Pro (c.289A>C) pathogenic?

INS p.Thr97Pro (c.289A>C) is classified Likely pathogenic in INS (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-30). AlphaMissense: ambiguous (0.437); Absent from gnomAD v4.1.

How common is INS p.Thr97Pro (c.289A>C) in the general population?

INS p.Thr97Pro (c.289A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about INS p.Thr97Pro (c.289A>C)?

AlphaMissense predicts ambiguous (score 0.437) — an in-silico prediction, not a clinical call.

INS p.Thr97Pro

c.289A>C · rs2133672927 · VCV1336487

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.437 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.437	ambiguous
REVEL	0.528	indeterminate
SaProt	LLR -9.61	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.34	GERP -0.96, phastCons 0.14
Regional constraint	o/e 0.05	constrained · MANE · 55 bp · p 1.6e-05 · regional, not allelic
Overall
CADD	22.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: INS
Protein: p.Thr97Pro
Coding: c.289A>C
MANE Select: NM_000207
dbSNP: rs2133672927
Type: single nucleotide variant
Location: chr11:2159896 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 53.19 · 386 PDB
Residue 97: an α-helix

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

Similar variants

INS c.-152C>A Pathogenic/Likely pathogenic ★★ same type
INS c.-152C>G Pathogenic ★★ same type
INS p.Ala24Val Likely pathogenic ★★ ⚠ same type
INS p.Arg89Cys Pathogenic/Likely pathogenic ★★ same type
INS p.Arg89His Pathogenic/Likely pathogenic ★★ same type
INS p.Gly32Ser Pathogenic/Likely pathogenic ★★ ⚠ same type
INS p.Met1Val Pathogenic/Likely pathogenic ★★ same type
INS p.Val42Ala Pathogenic/Likely 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/ins-p-thr97pro (accessed [today's date]).

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