Is TPX2 p.Ala142Val (c.425C>T) pathogenic?

TPX2 p.Ala142Val (c.425C>T) is classified Uncertain significance in TPX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: likely benign (0.1277); Very rare (popmax 0.00268%, afr).

How common is TPX2 p.Ala142Val (c.425C>T) in the general population?

TPX2 p.Ala142Val (c.425C>T) is very rare (popmax 0.00268%, afr) (gnomAD).

What do computational predictors say about TPX2 p.Ala142Val (c.425C>T)?

AlphaMissense predicts likely benign (score 0.1277) — an in-silico prediction, not a clinical call.

TPX2 p.Ala142Val

c.425C>T · VCV4598442

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1277 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00268%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1277	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -6.63	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 4.6	GERP 2.6, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 17 kb · p 0.28 · regional, not allelic
Overall
CADD	22.2	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

Grpmax group 0.00268% African / African-American · 2/74,626 alleles

Filtering AF 0.000445% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000167%

Overall 0.000311% 5/1,605,494 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00268%	37,313
European (non-Finnish)	0.000255%	391,820

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: TPX2
Protein: p.Ala142Val
Coding: c.425C>T
MANE Select: NM_012112
Type: single nucleotide variant
Location: chr20:31770411 (GRCh38)
Gene constraint: LOEUF 0.29 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 64.23 · 14 PDB
Residue 142: the 'disordered' region

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.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
TPX2 p.Arg296Gln 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-ala142val (accessed [today's date]).

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