Is INS p.Pro9Ser (c.25C>T) pathogenic?

INS p.Pro9Ser (c.25C>T) is classified Uncertain significance in INS (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-05-08). AlphaMissense: likely benign (0.3397); Ultra-rare (popmax 0.0134%, eas); Associated with INS-related disorder.

What condition is associated with INS p.Pro9Ser (c.25C>T)?

INS p.Pro9Ser (c.25C>T) is associated with INS-related disorder, type 1 diabetes mellitus 2, maturity-onset diabetes of the young type 10 (ClinVar).

How common is INS p.Pro9Ser (c.25C>T) in the general population?

INS p.Pro9Ser (c.25C>T) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about INS p.Pro9Ser (c.25C>T)?

AlphaMissense predicts likely benign (score 0.3397) — an in-silico prediction, not a clinical call.

INS p.Pro9Ser

c.25C>T · rs372122432 · VCV304058

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.3397 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

INS-related disorder

Computational evidence

Protein change
AlphaMissense	0.3397	likely benign
REVEL	0.428	indeterminate
SaProt	LLR -7.51	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -1.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 1,060 bp · p 0.36 · regional, not allelic
Overall
CADD	13.99	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% East Asian · 6/44,890 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.000682% 11/1,612,424 alleles · ultra-rare exomes 9/1,460,194 · genomes 2/152,230 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,482
Remaining individualsnot grpmax-eligible	0.00801%	12,487

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.Pro9Ser
Coding: c.25C>T
MANE Select: NM_000207
dbSNP: rs372122432
Type: single nucleotide variant
Location: chr11:2160947 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 53.19 · 386 PDB
Residue 9: an α-helix

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

Disease context

INS-related disorder

Also linked: type 1 diabetes mellitus 2 maturity-onset diabetes of the young type 10 hyperproinsulinemia diabetes mellitus, permanent neonatal 4

Similar variants

INS c.-152C>A Pathogenic/Likely pathogenic ★★ same condition
INS c.-152C>G Pathogenic ★★ same condition
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.Met1Val Pathogenic/Likely pathogenic ★★ same condition
INS p.Val42Ala Pathogenic/Likely pathogenic ★★ same condition
INS c.187+3G>A 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-pro9ser (accessed [today's date]).

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