Is INS p.Met1Val (c.1A>G) pathogenic?

INS p.Met1Val (c.1A>G) is classified Pathogenic/Likely pathogenic in INS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-13). Very rare (popmax 0.00223%, eas); Associated with type 1 diabetes mellitus 2.

What condition is associated with INS p.Met1Val (c.1A>G)?

INS p.Met1Val (c.1A>G) is associated with type 1 diabetes mellitus 2, maturity-onset diabetes of the young type 10, hyperproinsulinemia (ClinVar).

How common is INS p.Met1Val (c.1A>G) in the general population?

INS p.Met1Val (c.1A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

INS p.Met1Val

c.1A>G · rs757124361 · VCV1455986

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

type 1 diabetes mellitus 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.839	moderately pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.2, phastCons 1
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,880 alleles

Overall 0.000124% 2/1,612,114 alleles · very rare exomes 1/1,459,900 · genomes 1/152,214 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,880
European (non-Finnish)	8.48e-05%	1,179,754

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.Met1Val
Coding: c.1A>G
MANE Select: NM_000207
dbSNP: rs757124361
Type: single nucleotide variant
Location: chr11:2160971 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 53.19 · 386 PDB

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

Disease context

type 1 diabetes mellitus 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

INS p.Met1Ile Uncertain significance ★ same residue
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.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-met1val (accessed [today's date]).

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