Is ADAMTS6 p.Arg287Cys (c.859C>T) pathogenic?

ADAMTS6 p.Arg287Cys (c.859C>T) is classified Uncertain significance in ADAMTS6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-27). AlphaMissense: ambiguous (0.4925); Very rare (popmax 0.00501%, amr).

How common is ADAMTS6 p.Arg287Cys (c.859C>T) in the general population?

ADAMTS6 p.Arg287Cys (c.859C>T) is very rare (popmax 0.00501%, amr) (gnomAD).

What do computational predictors say about ADAMTS6 p.Arg287Cys (c.859C>T)?

AlphaMissense predicts ambiguous (score 0.4925) — an in-silico prediction, not a clinical call.

ADAMTS6 p.Arg287Cys

c.859C>T · VCV3491482

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4925 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00501%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4925	ambiguous
REVEL	0.811	moderately pathogenic-leaning
SaProt	LLR -14.08	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 153 kb · p 1.8e-14 · regional, not allelic
Overall
CADD	34.0	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 0.00501% Admixed American · 3/59,934 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00186% 30/1,612,424 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00501%	19,978
East Asian	0.00446%	22,411
European (non-Finnish)	0.00187%	53,596
Remaining individualsnot grpmax-eligible	0.0016%	62,412
Finnishnot grpmax-eligible	0.00156%	63,910
African / African-American	0.00134%	74,806

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: ADAMTS6
Protein: p.Arg287Cys
Coding: c.859C>T
MANE Select: NM_197941
Type: single nucleotide variant
Location: chr5:65452201 (GRCh38)
Gene constraint: LOEUF 0.228 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.45
Residue 287: the peptidase m12b domain

Full ADAMTS6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAMTS6 p.Met752Val Benign ★★ same type
ADAMTS6 p.Arg947Gln Likely pathogenic ★ ⚠ same type
ADAMTS6 c.844-4T>G Uncertain significance ★ same type
ADAMTS6 p.Ala437Thr Uncertain significance ★ ⚠ same type
ADAMTS6 p.Ala496Val Uncertain significance ★ ⚠ same type
ADAMTS6 p.Ala668Val Uncertain significance ★ ⚠ same type
ADAMTS6 p.Ala998Val Uncertain significance ★ ⚠ same type
ADAMTS6 p.Arg1009Gly 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/adamts6-p-arg287cys (accessed [today's date]).

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