Is TNKS2 p.His129Pro (c.386A>C) pathogenic?

TNKS2 p.His129Pro (c.386A>C) is classified Uncertain significance in TNKS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-04-24). AlphaMissense: likely pathogenic (0.9961); Absent from gnomAD v4.1.

How common is TNKS2 p.His129Pro (c.386A>C) in the general population?

TNKS2 p.His129Pro (c.386A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TNKS2 p.His129Pro (c.386A>C)?

AlphaMissense predicts likely pathogenic (score 0.9961) — an in-silico prediction, not a clinical call.

TNKS2 p.His129Pro

c.386A>C · VCV4908705

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9961 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9961	likely pathogenic
REVEL	0.91	moderately pathogenic-leaning
SaProt	LLR -15.92	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 30 kb · p 5.3e-05 · regional, not allelic
Overall
CADD	31.0	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: TNKS2
Protein: p.His129Pro
Coding: c.386A>C
MANE Select: NM_025235
Type: single nucleotide variant
Location: chr10:91813169 (GRCh38)
Gene constraint: LOEUF 0.713 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.76 · 201 PDB

Full TNKS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TNKS2 c.1673+17G>A Benign ★★ same type
TNKS2 c.424+20C>T Benign ★★ same type
TNKS2 p.Leu825= Benign ★★ same type
TNKS2 p.Ala1135Val Uncertain significance ★ same type
TNKS2 p.Ala1137Ser Uncertain significance ★ ⚠ same type
TNKS2 p.Ala239Gly Uncertain significance ★ ⚠ same type
TNKS2 p.Ala285Thr Uncertain significance ★ same type
TNKS2 p.Ala327Thr 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/tnks2-p-his129pro (accessed [today's date]).

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