Is TTBK2 p.Pro760Ser (c.2278C>T) pathogenic?

TTBK2 p.Pro760Ser (c.2278C>T) is classified Conflicting classifications of pathogenicity in TTBK2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-02). AlphaMissense: likely benign (0.0916); Ultra-rare (popmax 0.0891%, eas); Associated with Inborn genetic diseases.

What condition is associated with TTBK2 p.Pro760Ser (c.2278C>T)?

TTBK2 p.Pro760Ser (c.2278C>T) is associated with Inborn genetic diseases, spinocerebellar ataxia type 11 (ClinVar).

How common is TTBK2 p.Pro760Ser (c.2278C>T) in the general population?

TTBK2 p.Pro760Ser (c.2278C>T) is ultra-rare (popmax 0.0891%, eas) (gnomAD).

What do computational predictors say about TTBK2 p.Pro760Ser (c.2278C>T)?

AlphaMissense predicts likely benign (score 0.0916) — an in-silico prediction, not a clinical call.

TTBK2 p.Pro760Ser

c.2278C>T · rs117382379 · VCV315987

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0916 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0891%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0916	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -5.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP 0.69, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 49 kb · p 0.6 · regional, not allelic
Overall
CADD	12.92	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 0.0891% East Asian · 40/44,888 alleles

Filtering AF 0.0673% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0596%

Overall 0.0026% 42/1,614,172 alleles · ultra-rare exomes 35/1,461,880 · genomes 7/152,292 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0891%	1,122
Remaining individualsnot grpmax-eligible	0.0032%	31,254

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: TTBK2
Protein: p.Pro760Ser
Coding: c.2278C>T
MANE Select: NM_173500
dbSNP: rs117382379
Type: single nucleotide variant
Location: chr15:42752968 (GRCh38)
Gene constraint: LOEUF 0.326 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.55 · 7 PDB

Full TTBK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: spinocerebellar ataxia type 11

Similar variants

TTBK2 p.Ala1012Val Uncertain significance ★★ ⚠ same condition
TTBK2 p.Ala102Ser Uncertain significance ★★ ⚠ same condition
TTBK2 p.Ala102Val Uncertain significance ★★ ⚠ same condition
TTBK2 p.Ala197Thr Uncertain significance ★★ ⚠ same condition
TTBK2 p.Ala644Pro Uncertain significance ★★ ⚠ same condition
TTBK2 p.Arg1148His Uncertain significance ★★ ⚠ same condition
TTBK2 p.Arg1162Cys Uncertain significance ★★ same condition
TTBK2 p.Arg1173Gln Uncertain significance ★★ ⚠ same condition

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/ttbk2-p-pro760ser (accessed [today's date]).

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