Is INS p.Arg6His (c.17G>A) pathogenic?

INS p.Arg6His (c.17G>A) is classified Conflicting classifications of pathogenicity in INS (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-04-09). AlphaMissense: likely benign (0.2213); Ultra-rare (popmax 0.0574%, afr); Associated with INS-related disorder.

What condition is associated with INS p.Arg6His (c.17G>A)?

INS p.Arg6His (c.17G>A) 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.Arg6His (c.17G>A) in the general population?

INS p.Arg6His (c.17G>A) is ultra-rare (popmax 0.0574%, afr) (gnomAD).

What do computational predictors say about INS p.Arg6His (c.17G>A)?

AlphaMissense predicts likely benign (score 0.2213) — an in-silico prediction, not a clinical call.

INS p.Arg6His

c.17G>A · rs121908259 · VCV68727

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.2213 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0574%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

INS-related disorder

Computational evidence

Protein change
AlphaMissense	0.2213	likely benign
REVEL	0.586	indeterminate
SaProt	LLR -8.51	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.18	GERP -2.3, phastCons 0.016
Regional constraint	o/e 0.92	unconstrained · MANE · 1,060 bp · p 0.36 · regional, not allelic
Overall
CADD	16.6	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

Grpmax group 0.0574% African / African-American · 43/74,912 alleles

Filtering AF 0.0437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.039%

Overall 0.00986% 159/1,612,270 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0574%	1,742
Middle Eastern	0.0165%	6,050
South Asian	0.0143%	7,006
Remaining individualsnot grpmax-eligible	0.00801%	12,486
European (non-Finnish)	0.00788%	12,686
East Asian	0.00446%	22,437
Admixed American	0.00333%	29,985

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.Arg6His
Coding: c.17G>A
MANE Select: NM_000207
dbSNP: rs121908259
Type: single nucleotide variant
Location: chr11:2160955 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 53.19 · 386 PDB
Residue 6: a UniProt-annotated variant site (in mody10)

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-arg6his (accessed [today's date]).

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