Is ADAMTS19 p.Lys681Arg (c.2042A>G) pathogenic?

ADAMTS19 p.Lys681Arg (c.2042A>G) is classified Uncertain significance in ADAMTS19 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ADAMTS19 p.Lys681Arg (c.2042A>G)?

ADAMTS19 p.Lys681Arg (c.2042A>G) is associated with Inborn genetic diseases (ClinVar).

How common is ADAMTS19 p.Lys681Arg (c.2042A>G) in the general population?

ADAMTS19 p.Lys681Arg (c.2042A>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

ADAMTS19 p.Lys681Arg

c.2042A>G · VCV4230137

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.094	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 1.6, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 95 kb · p 5.6e-05 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,934 alleles

Overall 0.000137% 2/1,461,720 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
European (non-Finnish)grpmax	8.48e-05%	1,179,934

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ADAMTS19
Protein: p.Lys681Arg
Coding: c.2042A>G
MANE Select: NM_133638
Type: single nucleotide variant
Location: chr5:129648836 (GRCh38)
Gene constraint: LOEUF 0.83 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.76
Residue 681: a disulfide bond; a UniProt-annotated variant site (in cvdp2); the tsp type-1 1 domain

Full ADAMTS19 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

Similar variants

ADAMTS19 p.Phe414Leu Uncertain significance ★★ same condition
ADAMTS19 p.Ala1008Ser Uncertain significance ★ same condition
ADAMTS19 p.Ala1032Thr Uncertain significance ★ same condition
ADAMTS19 p.Ala164Val Uncertain significance ★ same condition
ADAMTS19 p.Ala213Ser Uncertain significance ★ same condition
ADAMTS19 p.Ala215Thr Uncertain significance ★ same condition
ADAMTS19 p.Ala215Val Uncertain significance ★ same condition
ADAMTS19 p.Ala220Glu 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/adamts19-p-lys681arg (accessed [today's date]).

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