Is TPX2 p.Pro326Ser (c.976C>T) pathogenic?

TPX2 p.Pro326Ser (c.976C>T) is classified Uncertain significance in TPX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-01). AlphaMissense: likely benign (0.1475); Absent from gnomAD v4.1.

How common is TPX2 p.Pro326Ser (c.976C>T) in the general population?

TPX2 p.Pro326Ser (c.976C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TPX2 p.Pro326Ser (c.976C>T)?

AlphaMissense predicts likely benign (score 0.1475) — an in-silico prediction, not a clinical call.

TPX2 p.Pro326Ser

c.976C>T · VCV3328378

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1475 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,612,210)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1475	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -8.62	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 2.6	GERP -0.41, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 23 kb · p 0.00012 · regional, not allelic
Overall
CADD	16.2	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

No allele count reported in gnomAD v4.1 (AN 1,612,210). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: TPX2
Protein: p.Pro326Ser
Coding: c.976C>T
MANE Select: NM_012112
Type: single nucleotide variant
Location: chr20:31778906 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.23 · 14 PDB

Full TPX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TPX2 p.Ala184= Benign ★★ same type
TPX2 p.Ser94= Benign ★★ same type
TPX2 p.Ala142Val Uncertain significance ★ ⚠ same type
TPX2 p.Ala184Gly Uncertain significance ★ ⚠ same type
TPX2 p.Ala668Val Uncertain significance ★ ⚠ same type
TPX2 p.Ala683Pro Uncertain significance ★ ⚠ same type
TPX2 p.Arg229Trp Uncertain significance ★ ⚠ same type
TPX2 p.Arg267Gln 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/tpx2-p-pro326ser (accessed [today's date]).

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