Is ADAMTS1 p.Pro173Ser (c.517C>T) pathogenic?

ADAMTS1 p.Pro173Ser (c.517C>T) is classified Uncertain significance in ADAMTS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: likely benign (0.0663); Very rare (popmax 8.57e-05%, nfe).

How common is ADAMTS1 p.Pro173Ser (c.517C>T) in the general population?

ADAMTS1 p.Pro173Ser (c.517C>T) is very rare (popmax 8.57e-05%, nfe) (gnomAD).

What do computational predictors say about ADAMTS1 p.Pro173Ser (c.517C>T)?

AlphaMissense predicts likely benign (score 0.0663) — an in-silico prediction, not a clinical call.

ADAMTS1 p.Pro173Ser

c.517C>T · VCV4637506

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0663 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.57e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0663	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	LLR -6.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -3
Regional constraint	o/e 1.16	unconstrained · MANE · 2,496 bp · p 0.00078 · regional, not allelic
Overall
CADD	1.257	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 8.57e-05% European (non-Finnish) · 1/1,167,292 alleles

Overall 6.97e-05% 1/1,435,616 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: ADAMTS1
Protein: p.Pro173Ser
Coding: c.517C>T
MANE Select: NM_006988
Type: single nucleotide variant
Location: chr21:26844438 (GRCh38)
Gene constraint: LOEUF 0.329 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.30 · 4 PDB

Full ADAMTS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAMTS1 c.1853-10C>G Benign ★★ same type
ADAMTS1 p.Arg383= Benign ★★ same type
ADAMTS1 p.Arg486= Benign ★★ same type
ADAMTS1 p.Arg756Gln Likely benign ★★ ⚠ same type
ADAMTS1 p.Asp782Gly Likely benign ★★ ⚠ same type
ADAMTS1 p.Glu631Lys Benign ★★ same type
ADAMTS1 p.Gly576Ser Likely benign ★★ ⚠ same type
ADAMTS1 p.Leu161= Benign ★★ 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/adamts1-p-pro173ser (accessed [today's date]).

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