Is TTK p.Gln249Pro (c.746A>C) pathogenic?

TTK p.Gln249Pro (c.746A>C) is classified Uncertain significance in TTK (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-08). AlphaMissense: likely benign (0.0801); Ultra-rare (popmax 0.0149%, nfe).

How common is TTK p.Gln249Pro (c.746A>C) in the general population?

TTK p.Gln249Pro (c.746A>C) is ultra-rare (popmax 0.0149%, nfe) (gnomAD).

What do computational predictors say about TTK p.Gln249Pro (c.746A>C)?

AlphaMissense predicts likely benign (score 0.0801) — an in-silico prediction, not a clinical call.

TTK p.Gln249Pro

c.746A>C · rs141417041 · VCV2348493

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0801 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0149%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0801	likely benign
REVEL	0.291	indeterminate
SaProt	LLR -5.54	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 0.47, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 36 kb · p 0.03 · regional, not allelic
Overall
CADD	23.8	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 0.0149% European (non-Finnish) · 176/1,179,198 alleles

Filtering AF 0.0131% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.0119% 192/1,612,786 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0149%	6,700
Remaining individualsnot grpmax-eligible	0.0144%	6,938
African / African-American	0.008%	12,499
Admixed American	0.00167%	59,852

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.Gln249Pro
Coding: c.746A>C
MANE Select: NM_003318
dbSNP: rs141417041
Type: single nucleotide variant
Location: chr6:80011746 (GRCh38)
Gene constraint: LOEUF 0.666 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.11 · 78 PDB

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-gln249pro (accessed [today's date]).

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