Is ADAMTS3 p.Pro960Ser (c.2878C>T) pathogenic?

ADAMTS3 p.Pro960Ser (c.2878C>T) is classified Uncertain significance in ADAMTS3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-26). AlphaMissense: likely benign (0.0974); Absent from gnomAD v4.1; Associated with hennekam lymphangiectasia-lymphedema syndrome 3.

What condition is associated with ADAMTS3 p.Pro960Ser (c.2878C>T)?

ADAMTS3 p.Pro960Ser (c.2878C>T) is associated with hennekam lymphangiectasia-lymphedema syndrome 3 (ClinVar).

How common is ADAMTS3 p.Pro960Ser (c.2878C>T) in the general population?

ADAMTS3 p.Pro960Ser (c.2878C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ADAMTS3 p.Pro960Ser (c.2878C>T)?

AlphaMissense predicts likely benign (score 0.0974) — an in-silico prediction, not a clinical call.

ADAMTS3 p.Pro960Ser

c.2878C>T · rs1718640685 · VCV3065425

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0974 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hennekam lymphangiectasia-lymphedema syndrome 3

Computational evidence

Protein change
AlphaMissense	0.0974	likely benign
REVEL	0.11	moderately benign-leaning
SaProt	LLR -2.62	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 5	GERP 0.45, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 286 kb · p 0.14 · regional, not allelic
Overall
CADD	20.1	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

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: ADAMTS3
Protein: p.Pro960Ser
Coding: c.2878C>T
MANE Select: NM_014243
dbSNP: rs1718640685
Type: single nucleotide variant
Location: chr4:72290908 (GRCh38)
Gene constraint: LOEUF 0.67 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.31
Residue 960: the tsp type-1 3 domain

Full ADAMTS3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hennekam lymphangiectasia-lymphedema syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ADAMTS3 p.Arg1035Gln Uncertain significance ★★ ⚠ same condition
ADAMTS3 p.Asn1016Ser Uncertain significance ★★ ⚠ same condition
ADAMTS3 c.2179+21G>A Benign ★★ same condition
ADAMTS3 c.661+7G>A Benign/Likely benign ★★ same condition
ADAMTS3 p.Arg138Lys Benign ★★ same condition
ADAMTS3 p.Arg94Ter Pathogenic ★ same condition
ADAMTS3 p.Ala169Thr Uncertain significance ★ ⚠ same condition
ADAMTS3 p.Arg817Gly 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/adamts3-p-pro960ser (accessed [today's date]).

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