Is ADAMTS17 p.Arg421= (c.1263G>C) pathogenic?

ADAMTS17 p.Arg421= (c.1263G>C) is classified Likely benign in ADAMTS17 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-27). Very rare (popmax 0.000339%, nfe).

How common is ADAMTS17 p.Arg421= (c.1263G>C) in the general population?

ADAMTS17 p.Arg421= (c.1263G>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

ADAMTS17 p.Arg421=

c.1263G>C · rs747285202 · VCV2794798

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

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 0.28	GERP -2.6, phastCons 0.98
Overall
CADD	7.903	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,056 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000805% 13/1,614,086 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00937%	10,673
Remaining individualsnot grpmax-eligible	0.0048%	20,829
European (non-Finnish)grpmax	0.000339%	295,014

Finnish 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: ADAMTS17
Protein: p.Arg421=
Coding: c.1263G>C
MANE Select: NM_139057
dbSNP: rs747285202
Type: single nucleotide variant
Location: chr15:100155239 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 70.06
Residue 421: a disulfide bond; the peptidase m12b domain

Full ADAMTS17 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAMTS17 p.Arg421Gln Uncertain significance ★★ ⚠ same residue
ADAMTS17 c.1576-1G>T Likely pathogenic ★★ same type
ADAMTS17 p.Arg433Ter Pathogenic/Likely pathogenic ★★ same type
ADAMTS17 p.Arg854Ter Pathogenic/Likely pathogenic ★★ same type
ADAMTS17 p.Ser971Ter Pathogenic/Likely pathogenic ★★ same type
ADAMTS17 c.2017-3T>C Uncertain significance ★★ same type
ADAMTS17 c.2295+3A>G Uncertain significance ★★ same type
ADAMTS17 c.79+3A>C Uncertain significance ★★ same type

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/adamts17-p-arg421 (accessed [today's date]).

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