Is ADAMTS4 p.Arg696= (c.2088G>A) pathogenic?

ADAMTS4 p.Arg696= (c.2088G>A) is classified Likely benign in ADAMTS4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-10). Very rare (popmax 0.00017%, nfe).

How common is ADAMTS4 p.Arg696= (c.2088G>A) in the general population?

ADAMTS4 p.Arg696= (c.2088G>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

ADAMTS4 p.Arg696=

c.2088G>A · VCV4008757

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00017%, 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 3.3	GERP 0.69, phastCons 1
Overall
CADD	13.52	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,173,816 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000125% 2/1,604,016 alleles · very rare

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: ADAMTS4
Protein: p.Arg696=
Coding: c.2088G>A
MANE Select: NM_005099
Type: single nucleotide variant
Location: chr1:161191564 (GRCh38)
Gene constraint: LOEUF 0.732 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.80 · 5 PDB
Residue 696: the 'spacer' region

Full ADAMTS4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAMTS4 c.*56A>G Benign ★★ same type
ADAMTS4 p.Ala115Val Uncertain significance ★ ⚠ same type
ADAMTS4 p.Ala20Ser Uncertain significance ★ ⚠ same type
ADAMTS4 p.Ala236Val Uncertain significance ★ ⚠ same type
ADAMTS4 p.Ala252Asp Uncertain significance ★ ⚠ same type
ADAMTS4 p.Ala286Val Uncertain significance ★ ⚠ same type
ADAMTS4 p.Ala313Gly Uncertain significance ★ ⚠ same type
ADAMTS4 p.Ala430Thr 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/adamts4-p-arg696 (accessed [today's date]).

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