Is INS p.Pro21= (c.63A>G) pathogenic?

INS p.Pro21= (c.63A>G) is classified Conflicting classifications of pathogenicity in INS (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-11-24). Low-frequency (popmax 1.72%, afr); Associated with Inborn genetic diseases.

What condition is associated with INS p.Pro21= (c.63A>G)?

INS p.Pro21= (c.63A>G) is associated with Inborn genetic diseases, maturity-onset diabetes of the young type 10 (ClinVar).

How common is INS p.Pro21= (c.63A>G) in the general population?

INS p.Pro21= (c.63A>G) is low-frequency (popmax 1.72%, afr) (gnomAD).

INS p.Pro21=

c.63A>G · rs11564720 · VCV255533

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.72%, afr)

Conditions

Inborn genetic diseases

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 -20	GERP -2
Overall
CADD	0.011	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.72% African / African-American · 1,288/75,048 alleles

Filtering AF 1.64% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.61%

Overall 0.111% 1,786/1,612,630 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.72%	58
Remaining individualsnot grpmax-eligible	0.173%	578
Middle Eastern	0.165%	606
Admixed American	0.143%	698
European (non-Finnish)	0.0242%	4,125
South Asian	0.00439%	22,770
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,588
Finnishnot grpmax-eligible	0.00319%	31,374
East Asian	0.00223%	44,876

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.Pro21=
Coding: c.63A>G
MANE Select: NM_000207
dbSNP: rs11564720
Type: single nucleotide variant
Location: chr11:2160909 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 53.19 · 386 PDB
Residue 21: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: maturity-onset diabetes of the young type 10

Similar variants

INS c.-152C>A Pathogenic/Likely pathogenic ★★ same condition
INS c.-152C>G Pathogenic ★★ same condition
INS p.Arg89His 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
INS c.-152C>T Uncertain significance ★★ same condition
INS p.Ala12Val 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-pro21 (accessed [today's date]).

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