Is TTK p.Ser712Ile (c.2135G>T) pathogenic?

TTK p.Ser712Ile (c.2135G>T) is classified Uncertain significance in TTK (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-03). AlphaMissense: likely pathogenic (0.7562); Very rare (popmax 8.82e-05%, nfe).

How common is TTK p.Ser712Ile (c.2135G>T) in the general population?

TTK p.Ser712Ile (c.2135G>T) is very rare (popmax 8.82e-05%, nfe) (gnomAD).

What do computational predictors say about TTK p.Ser712Ile (c.2135G>T)?

AlphaMissense predicts likely pathogenic (score 0.7562) — an in-silico prediction, not a clinical call.

TTK p.Ser712Ile

c.2135G>T · rs1767995697 · VCV2322459

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7562 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.82e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7562	likely pathogenic
REVEL	0.826	moderately pathogenic-leaning
SaProt	LLR -10.46	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 12	GERP 0.67, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 36 kb · p 0.03 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 8.82e-05% European (non-Finnish) · 1/1,133,632 alleles

Overall 7.37e-05% 1/1,356,564 alleles · very 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: TTK
Protein: p.Ser712Ile
Coding: c.2135G>T
MANE Select: NM_003318
dbSNP: rs1767995697
Type: single nucleotide variant
Location: chr6:80039700 (GRCh38)
Gene constraint: LOEUF 0.666 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.11 · 78 PDB
Residue 712: the protein kinase domain

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

Similar variants

TTK p.Thr423= Likely benign ★★ same type
TTK p.Ala110Pro Uncertain significance ★ ⚠ same type
TTK p.Ala251Gly Uncertain significance ★ ⚠ same type
TTK p.Ala401Pro Uncertain significance ★ ⚠ same type
TTK p.Ala402Val Uncertain significance ★ ⚠ same type
TTK p.Ala787Gly Uncertain significance ★ ⚠ same type
TTK p.Arg129Cys Uncertain significance ★ ⚠ same type
TTK p.Arg256Pro 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/ttk-p-ser712ile (accessed [today's date]).

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