Is ADAMTS5 p.Pro752Ser (c.2254C>T) pathogenic?

ADAMTS5 p.Pro752Ser (c.2254C>T) is classified Uncertain significance in ADAMTS5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: likely pathogenic (0.7208); Absent from gnomAD v4.1.

How common is ADAMTS5 p.Pro752Ser (c.2254C>T) in the general population?

ADAMTS5 p.Pro752Ser (c.2254C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ADAMTS5 p.Pro752Ser (c.2254C>T)?

AlphaMissense predicts likely pathogenic (score 0.7208) — an in-silico prediction, not a clinical call.

ADAMTS5 p.Pro752Ser

c.2254C>T · VCV4637670

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7208 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7208	likely pathogenic
REVEL	0.715	pathogenic-leaning
SaProt	LLR -12.08	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 41 kb · p 2.1e-05 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ADAMTS5
Protein: p.Pro752Ser
Coding: c.2254C>T
MANE Select: NM_007038
Type: single nucleotide variant
Location: chr21:26924592 (GRCh38)
Gene constraint: LOEUF 0.818 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.07 · 8 PDB
Residue 752: the 'spacer' region

Full ADAMTS5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAMTS5 p.Arg614His Benign ★★ ⚠ same type
ADAMTS5 p.Gly284= Likely benign ★★ same type
ADAMTS5 p.His310Tyr Benign ★★ same type
ADAMTS5 p.Leu244Phe Benign ★★ ⚠ same type
ADAMTS5 p.Leu692= Benign ★★ same type
ADAMTS5 p.Leu692Pro Benign ★★ same type
ADAMTS5 p.Ala116Val Uncertain significance ★ ⚠ same type
ADAMTS5 p.Ala122Val Uncertain significance ★ ⚠ 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/adamts5-p-pro752ser (accessed [today's date]).

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