Is ADAMTS8 p.Arg622Pro (c.1865G>C) pathogenic?

ADAMTS8 p.Arg622Pro (c.1865G>C) is classified Uncertain significance in ADAMTS8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: likely pathogenic (0.9388); Very rare (popmax 0.000169%, nfe).

How common is ADAMTS8 p.Arg622Pro (c.1865G>C) in the general population?

ADAMTS8 p.Arg622Pro (c.1865G>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about ADAMTS8 p.Arg622Pro (c.1865G>C)?

AlphaMissense predicts likely pathogenic (score 0.9388) — an in-silico prediction, not a clinical call.

ADAMTS8 p.Arg622Pro

c.1865G>C · VCV4637739

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9388 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9388	likely pathogenic · top 8% in ADAMTS8
REVEL	0.335	indeterminate
SaProt	LLR -15.40	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 5,608 bp · p 0.65 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,996 alleles

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

Overall 0.000124% 2/1,613,880 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: ADAMTS8
Protein: p.Arg622Pro
Coding: c.1865G>C
MANE Select: NM_007037
Type: single nucleotide variant
Location: chr11:130408826 (GRCh38)
Gene constraint: LOEUF 1.076 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.22

Full ADAMTS8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAMTS8 p.Ala114Val Uncertain significance ★ ⚠ same type
ADAMTS8 p.Ala115Glu Uncertain significance ★ ⚠ same type
ADAMTS8 p.Ala335Thr Uncertain significance ★ ⚠ same type
ADAMTS8 p.Ala33Thr Uncertain significance ★ ⚠ same type
ADAMTS8 p.Ala37Thr Uncertain significance ★ ⚠ same type
ADAMTS8 p.Ala428Asp Uncertain significance ★ ⚠ same type
ADAMTS8 p.Ala431Val Uncertain significance ★ ⚠ same type
ADAMTS8 p.Ala473Thr 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/adamts8-p-arg622pro (accessed [today's date]).

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