Is ADAMTSL2 p.Pro85= (c.255C>T) pathogenic?

ADAMTSL2 p.Pro85= (c.255C>T) is classified Uncertain significance in ADAMTSL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Ultra-rare (popmax 0.0317%, amr); Associated with geleophysic dysplasia 1.

What condition is associated with ADAMTSL2 p.Pro85= (c.255C>T)?

ADAMTSL2 p.Pro85= (c.255C>T) is associated with geleophysic dysplasia 1 (ClinVar).

How common is ADAMTSL2 p.Pro85= (c.255C>T) in the general population?

ADAMTSL2 p.Pro85= (c.255C>T) is ultra-rare (popmax 0.0317%, amr) (gnomAD).

ADAMTSL2 p.Pro85=

c.255C>T · rs777495910 · VCV365572

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0317%, amr)

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 -16	GERP -2.6
Overall
CADD	0.304	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0317% Admixed American · 19/60,010 alleles

Filtering AF 0.0207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.00242% 39/1,613,212 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0317%	3,158
East Asian	0.00891%	11,221
South Asian	0.00329%	30,365
Remaining individualsnot grpmax-eligible	0.0016%	62,480
African / African-American	0.00133%	74,934
European (non-Finnish)	0.000932%	107,276

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.Pro85=
Coding: c.255C>T
MANE Select: NM_014694
dbSNP: rs777495910
Type: single nucleotide variant
Location: chr9:133538370 (GRCh38)
Gene constraint: LOEUF 0.679 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 67.10
Residue 85: the tsp type-1 1 domain; a disulfide bond

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-pro85 (accessed [today's date]).

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