Is ADAMTS13 p.Ala321Pro (c.961G>C) pathogenic?

ADAMTS13 p.Ala321Pro (c.961G>C) is classified Uncertain significance in ADAMTS13 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-28). AlphaMissense: likely benign (0.1696); Ultra-rare (popmax 0.0472%, amr); Associated with Inborn genetic diseases.

What condition is associated with ADAMTS13 p.Ala321Pro (c.961G>C)?

ADAMTS13 p.Ala321Pro (c.961G>C) is associated with Inborn genetic diseases, congenital thrombotic thrombocytopenic purpura (ClinVar).

How common is ADAMTS13 p.Ala321Pro (c.961G>C) in the general population?

ADAMTS13 p.Ala321Pro (c.961G>C) is ultra-rare (popmax 0.0472%, amr) (gnomAD).

What do computational predictors say about ADAMTS13 p.Ala321Pro (c.961G>C)?

AlphaMissense predicts likely benign (score 0.1696) — an in-silico prediction, not a clinical call.

ADAMTS13 p.Ala321Pro

c.961G>C · VCV3596638

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1696 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0472%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1696	likely benign
REVEL	0.521	indeterminate
SaProt	LLR -7.69	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.4	GERP -0.82, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 16 kb · p 0.54 · regional, not allelic
Overall
CADD	25.6	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

Grpmax group 0.0472% Admixed American · 28/59,266 alleles

Filtering AF 0.0335% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.029%

Overall 0.00176% 28/1,593,994 alleles · ultra-rare

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: ADAMTS13
Protein: p.Ala321Pro
Coding: c.961G>C
MANE Select: NM_139027
Type: single nucleotide variant
Location: chr9:133430075 (GRCh38)
Gene constraint: LOEUF 0.917 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 76.00 · 5 PDB
Residue 321: the disintegrin domain; a disulfide bond

Full ADAMTS13 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: congenital thrombotic thrombocytopenic purpura

Similar variants

ADAMTS13 c.1705+1G>A Likely pathogenic ★★ same condition
ADAMTS13 c.330+1G>A Pathogenic/Likely pathogenic ★★ same condition
ADAMTS13 p.Ala596Val Pathogenic ★★ same condition
ADAMTS13 p.Ala690Thr Likely pathogenic ★★ ⚠ same condition
ADAMTS13 p.Arg102Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
ADAMTS13 p.Arg102His Likely pathogenic ★★ ⚠ same condition
ADAMTS13 p.Arg1060Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
ADAMTS13 p.Arg1123Cys Pathogenic/Likely pathogenic ★★ ⚠ 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/adamts13-p-ala321pro (accessed [today's date]).

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