Is ADAMTSL2 p.Pro683= (c.2049C>T) pathogenic?

ADAMTSL2 p.Pro683= (c.2049C>T) is classified Conflicting classifications of pathogenicity in ADAMTSL2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-05-11). Common (popmax 6.34%, afr) — too common for a highly-penetrant pathogenic allele; Associated with geleophysic dysplasia 1.

What condition is associated with ADAMTSL2 p.Pro683= (c.2049C>T)?

ADAMTSL2 p.Pro683= (c.2049C>T) is associated with geleophysic dysplasia 1 (ClinVar).

ADAMTSL2 p.Pro683=

Q: How common is ADAMTSL2 p.Pro683= (c.2049C>T) in the general population?

ADAMTSL2 p.Pro683= (c.2049C>T) is common (popmax 6.34%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2049C>T · rs886063644 · VCV365601

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 6.34%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

geleophysic dysplasia 1

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 -6.2	GERP -1.2
Overall
CADD	6.994	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.34% African / African-American · 4,759/75,008 alleles

Filtering AF 6.19% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.13%

Overall 0.366% 5,886/1,608,108 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.34%	16
Middle Eastern	0.846%	118
Ashkenazi Jewishnot grpmax-eligible	0.837%	119
Admixed American	0.475%	210
Remaining individualsnot grpmax-eligible	0.473%	211
European (non-Finnish)	0.0205%	4,868
South Asian	0.00777%	12,876
Finnishnot grpmax-eligible	0.00322%	31,027
East Asian	0.00224%	44,636

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: ADAMTSL2
Protein: p.Pro683=
Coding: c.2049C>T
MANE Select: NM_014694
dbSNP: rs886063644
Type: single nucleotide variant
Location: chr9:133568447 (GRCh38)
Gene constraint: LOEUF 0.679 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 67.10
Residue 683: the tsp type-1 3 domain

Full ADAMTSL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

geleophysic dysplasia 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ADAMTSL2 p.Arg113Cys Likely pathogenic ★★ same condition
ADAMTSL2 p.Arg113His Likely pathogenic ★★ same condition
ADAMTSL2 p.Arg113Leu Likely pathogenic ★★ same condition
ADAMTSL2 p.Arg177Ter Pathogenic/Likely pathogenic ★★ same condition
ADAMTSL2 p.Arg425Gln Uncertain significance ★★ ⚠ same condition
ADAMTSL2 p.Arg4Thr Uncertain significance ★★ ⚠ same condition
ADAMTSL2 p.Arg681Gln Uncertain significance ★★ ⚠ same condition
ADAMTSL2 p.Glu327Lys 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/adamtsl2-p-pro683 (accessed [today's date]).

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