Is ADAMTS17 p.Pro45Ser (c.133C>T) pathogenic?

ADAMTS17 p.Pro45Ser (c.133C>T) is classified Uncertain significance in ADAMTS17 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-01). AlphaMissense: likely benign (0.1052); Very rare (popmax 0.00668%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ADAMTS17 p.Pro45Ser (c.133C>T)?

ADAMTS17 p.Pro45Ser (c.133C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ADAMTS17 p.Pro45Ser (c.133C>T) in the general population?

ADAMTS17 p.Pro45Ser (c.133C>T) is very rare (popmax 0.00668%, nfe) (gnomAD).

What do computational predictors say about ADAMTS17 p.Pro45Ser (c.133C>T)?

AlphaMissense predicts likely benign (score 0.1052) — an in-silico prediction, not a clinical call.

ADAMTS17 p.Pro45Ser

c.133C>T · rs990567774 · VCV2195405

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1052 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1052	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -9.56	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 8.9	GERP 0.58, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 367 kb · p 0.00029 · regional, not allelic
Overall
CADD	17.53	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 0.00668% European (non-Finnish) · 57/853,706 alleles

Filtering AF 0.00522% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00476%

Overall 0.00697% 71/1,018,480 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0349%	2,868
European (non-Finnish)grpmax	0.00668%	14,977
African / African-American	0.00522%	19,147

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ADAMTS17
Protein: p.Pro45Ser
Coding: c.133C>T
MANE Select: NM_139057
dbSNP: rs990567774
Type: single nucleotide variant
Location: chr15:100341356 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 70.06

Full ADAMTS17 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ADAMTS17 p.Pro45= Likely benign ★ same residue
ADAMTS17 p.Ala194Val Uncertain significance ★★ ⚠ same condition
ADAMTS17 p.Ala242Ser Uncertain significance ★★ ⚠ same condition
ADAMTS17 p.Ala253Ser Uncertain significance ★★ ⚠ same condition
ADAMTS17 p.Ala590Val Uncertain significance ★★ ⚠ same condition
ADAMTS17 p.Ala683Thr Uncertain significance ★★ ⚠ same condition
ADAMTS17 p.Ala70Gly Uncertain significance ★★ ⚠ same condition
ADAMTS17 p.Ala71Ser Uncertain significance ★★ ⚠ same condition

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/adamts17-p-pro45ser (accessed [today's date]).

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