Is TTK p.Leu70Phe (c.208C>T) pathogenic?

TTK p.Leu70Phe (c.208C>T) is classified Uncertain significance in TTK (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-27). AlphaMissense: likely benign (0.1533); Ultra-rare (popmax 0.0384%, sas).

How common is TTK p.Leu70Phe (c.208C>T) in the general population?

TTK p.Leu70Phe (c.208C>T) is ultra-rare (popmax 0.0384%, sas) (gnomAD).

What do computational predictors say about TTK p.Leu70Phe (c.208C>T)?

AlphaMissense predicts likely benign (score 0.1533) — an in-silico prediction, not a clinical call.

TTK p.Leu70Phe

c.208C>T · rs763634581 · VCV2252283

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1533 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0384%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1533	likely benign
REVEL	0.444	indeterminate
SaProt	LLR -9.08	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 3.3	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 36 kb · p 0.03 · regional, not allelic
Overall
CADD	24.3	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 0.0384% South Asian · 35/91,034 alleles

Filtering AF 0.0283% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0249%

Overall 0.00267% 43/1,613,128 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0384%	2,601
Middle Eastern	0.0165%	6,078
European (non-Finnish)	0.000593%	168,501

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.Leu70Phe
Coding: c.208C>T
MANE Select: NM_003318
dbSNP: rs763634581
Type: single nucleotide variant
Location: chr6:80007877 (GRCh38)
Gene constraint: LOEUF 0.666 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.11 · 78 PDB
Residue 70: an α-helix

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-leu70phe (accessed [today's date]).

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