Is ADAMTS17 p.Val336= (c.1008G>A) pathogenic?

ADAMTS17 p.Val336= (c.1008G>A) is classified Conflicting classifications of pathogenicity in ADAMTS17 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-08). Ultra-rare (popmax 0.03%, amr); Associated with Weill-Marchesani 4 syndrome, recessive.

What condition is associated with ADAMTS17 p.Val336= (c.1008G>A)?

ADAMTS17 p.Val336= (c.1008G>A) is associated with Weill-Marchesani 4 syndrome, recessive (ClinVar).

How common is ADAMTS17 p.Val336= (c.1008G>A) in the general population?

ADAMTS17 p.Val336= (c.1008G>A) is ultra-rare (popmax 0.03%, amr) (gnomAD).

ADAMTS17 p.Val336=

Q: How is Ichthyosis-short stature-brachydactyly-microspherophakia syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1008G>A · rs557358714 · VCV315305

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.03%, amr)

Conditions

Weill-Marchesani 4 syndrome, recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 0.5, phastCons 1
Overall
CADD	12.84	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.03% Admixed American · 18/60,028 alleles

Filtering AF 0.0194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.00297% 48/1,614,172 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.03%	3,335
Remaining individualsnot grpmax-eligible	0.0048%	20,836
European (non-Finnish)	0.0022%	45,386
African / African-American	0.00133%	75,046

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.Val336=
Coding: c.1008G>A
MANE Select: NM_139057
dbSNP: rs557358714
Type: single nucleotide variant
Location: chr15:100261502 (GRCh38)
Gene constraint: LOEUF 0.966 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 70.06
Residue 336: a disulfide bond; the peptidase m12b domain

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

Disease context

Weill-Marchesani 4 syndrome, recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Ichthyosis-short stature-brachydactyly-microspherophakia syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

ADAMTS17 p.Val336Met Uncertain significance ★ same residue
ADAMTS17 c.1576-1G>T Likely pathogenic ★★ same condition
ADAMTS17 p.Arg433Ter Pathogenic/Likely pathogenic ★★ same condition
ADAMTS17 p.Arg854Ter Pathogenic/Likely pathogenic ★★ same condition
ADAMTS17 c.2017-3T>C Uncertain significance ★★ same condition
ADAMTS17 c.2295+3A>G Uncertain significance ★★ same condition
ADAMTS17 c.79+3A>C Uncertain significance ★★ same condition
ADAMTS17 c.-69C>T 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-val336 (accessed [today's date]).

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