Is INS p.His34Pro (c.101A>C) pathogenic?

INS p.His34Pro (c.101A>C) is classified Likely pathogenic in INS (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.6694); Absent from gnomAD v4.1; Associated with neonatal diabetes mellitus.

What condition is associated with INS p.His34Pro (c.101A>C)?

INS p.His34Pro (c.101A>C) is associated with neonatal diabetes mellitus (ClinVar).

How common is INS p.His34Pro (c.101A>C) in the general population?

INS p.His34Pro (c.101A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about INS p.His34Pro (c.101A>C)?

AlphaMissense predicts likely pathogenic (score 0.6694) — an in-silico prediction, not a clinical call.

INS p.His34Pro

c.101A>C · rs1564912274 · VCV1526012

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6694 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neonatal diabetes mellitus

Computational evidence

Protein change
AlphaMissense	0.6694	likely pathogenic ✓ concordant with ClinVar
REVEL	0.829	moderately pathogenic-leaning
SaProt	LLR -8.31	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 1,060 bp · p 0.36 · regional, not allelic
Overall
CADD	26.1	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.His34Pro
Coding: c.101A>C
MANE Select: NM_000207
dbSNP: rs1564912274
Type: single nucleotide variant
Location: chr11:2160871 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 53.19 · 386 PDB
Residue 34: a UniProt-annotated variant site (in hpri; providence); an α-helix

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

Disease context

neonatal diabetes mellitus — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

INS p.His34Arg Uncertain significance ★ ⚠ same residue
INS p.His34Asp Uncertain significance ★ ⚠ same residue
INS p.Ala24Val Likely pathogenic ★★ ⚠ same condition
INS p.Arg89Cys Pathogenic/Likely pathogenic ★★ same condition
INS p.Gly32Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
INS c.188-16C>T Benign/Likely benign ★★ same condition
INS c.-9C>T Benign/Likely benign ★★ same condition
INS p.Leu35Met 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-his34pro (accessed [today's date]).

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