Is TTK p.Pro757Ser (c.2269C>T) pathogenic?

TTK p.Pro757Ser (c.2269C>T) is classified Uncertain significance in TTK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-20). AlphaMissense: likely benign (0.325); Rare (popmax 0.136%, sas).

How common is TTK p.Pro757Ser (c.2269C>T) in the general population?

TTK p.Pro757Ser (c.2269C>T) is rare (popmax 0.136%, sas) (gnomAD).

What do computational predictors say about TTK p.Pro757Ser (c.2269C>T)?

AlphaMissense predicts likely benign (score 0.325) — an in-silico prediction, not a clinical call.

TTK p.Pro757Ser

c.2269C>T · VCV3812057

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.325 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.136%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.325	likely benign
REVEL	0.568	indeterminate
SaProt	LLR -10.56	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP -0.11, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 36 kb · p 0.03 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.136% South Asian · 114/83,784 alleles

Filtering AF 0.116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.108%

Overall 0.0128% 202/1,582,586 alleles · rare exomes 192/1,431,008 · genomes 10/151,578 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.136%	735
Middle Eastern	0.068%	1,471
Remaining individualsnot grpmax-eligible	0.00819%	12,215
European (non-Finnish)	0.0066%	15,155
Admixed American	0.00365%	27,397

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.Pro757Ser
Coding: c.2269C>T
MANE Select: NM_003318
Type: single nucleotide variant
Location: chr6:80039834 (GRCh38)
Gene constraint: LOEUF 0.666 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.11 · 78 PDB
Residue 757: 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-pro757ser (accessed [today's date]).

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