Is ADAMTS4 p.Pro406Ser (c.1216C>T) pathogenic?

ADAMTS4 p.Pro406Ser (c.1216C>T) is classified Uncertain significance in ADAMTS4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-24). AlphaMissense: likely benign (0.1076); Very rare (popmax 8.48e-05%, nfe).

How common is ADAMTS4 p.Pro406Ser (c.1216C>T) in the general population?

ADAMTS4 p.Pro406Ser (c.1216C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ADAMTS4 p.Pro406Ser (c.1216C>T)?

AlphaMissense predicts likely benign (score 0.1076) — an in-silico prediction, not a clinical call.

ADAMTS4 p.Pro406Ser

c.1216C>T · VCV4231083

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1076 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1076	likely benign
REVEL	0.187	benign-leaning
SaProt	LLR -10.96	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 7,486 bp · p 0.0021 · regional, not allelic
Overall
CADD	23.9	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 8.48e-05% European (non-Finnish) · 1/1,179,730 alleles

Overall 6.84e-05% 1/1,461,286 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.Pro406Ser
Coding: c.1216C>T
MANE Select: NM_005099
Type: single nucleotide variant
Location: chr1:161195510 (GRCh38)
Gene constraint: LOEUF 0.732 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.80 · 5 PDB
Residue 406: a disulfide bond; the peptidase m12b domain; an α-helix

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

Similar variants

ADAMTS4 p.Pro406Leu Uncertain significance ★ ⚠ same residue
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

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-pro406ser (accessed [today's date]).

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