Is INS p.Ala22= (c.66C>T) pathogenic?

INS p.Ala22= (c.66C>T) is classified Likely benign in INS (ClinVar, Single submitter, 1 submitter). Ultra-rare (popmax 0.0165%, mid); Associated with Neonatal insulin-dependent diabetes mellitus.

What condition is associated with INS p.Ala22= (c.66C>T)?

INS p.Ala22= (c.66C>T) is associated with Neonatal insulin-dependent diabetes mellitus (ClinVar).

How common is INS p.Ala22= (c.66C>T) in the general population?

INS p.Ala22= (c.66C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

INS p.Ala22=

c.66C>T · rs375371953 · VCV304056

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

Neonatal insulin-dependent diabetes mellitus

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.59	GERP -2, phastCons 0.001
Overall
CADD	8.594	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,076 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000806% 13/1,612,534 alleles · ultra-rare exomes 11/1,460,322 · genomes 2/152,212 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,076
Admixed American	0.005%	19,999
African / African-American	0.00267%	37,468
European (non-Finnish)	0.000593%	168,551

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.Ala22=
Coding: c.66C>T
MANE Select: NM_000207
dbSNP: rs375371953
Type: single nucleotide variant
Location: chr11:2160906 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 53.19 · 386 PDB
Residue 22: an α-helix

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

Disease context

Neonatal insulin-dependent diabetes mellitus — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

INS c.188-220C>T Benign/Likely benign ★★ same condition
INS c.-18+21C>T Benign/Likely benign ★★ same condition
TH c.*277G>A Benign/Likely benign ★★ same condition
TH p.Thr426= Benign/Likely benign ★★ same condition
INS p.Pro52Arg Likely pathogenic ★ ⚠ same condition
INS c.188-96G>A Conflicting classifications of pathogenicity ★ same condition
INS c.-18+22G>A Conflicting classifications of pathogenicity ★ same condition
INS c.-39A>C Conflicting classifications of pathogenicity ★ 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-ala22 (accessed [today's date]).

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