Is TTBK1 p.Val593Ile (c.1777G>A) pathogenic?

TTBK1 p.Val593Ile (c.1777G>A) is classified Uncertain significance in TTBK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-28). AlphaMissense: likely benign (0.0991); Very rare (popmax 0.000433%, nfe).

How common is TTBK1 p.Val593Ile (c.1777G>A) in the general population?

TTBK1 p.Val593Ile (c.1777G>A) is very rare (popmax 0.000433%, nfe) (gnomAD).

What do computational predictors say about TTBK1 p.Val593Ile (c.1777G>A)?

AlphaMissense predicts likely benign (score 0.0991) — an in-silico prediction, not a clinical call.

TTBK1 p.Val593Ile

c.1777G>A · rs1173499881 · VCV2340352

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0991 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000433%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0991	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -7.92	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.9	GERP 0.22, phastCons 0.96
Regional constraint	o/e 0.97	unconstrained · MANE · 22 kb · p 0.34 · regional, not allelic
Overall
CADD	18.47	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 0.000433% European (non-Finnish) · 5/1,154,938 alleles

Filtering AF 0.000127% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.2e-05%

Overall 0.000319% 5/1,567,252 alleles · very rare exomes 5/1,414,956 · genomes 0/152,296 · joint denominator

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: TTBK1
Protein: p.Val593Ile
Coding: c.1777G>A
MANE Select: NM_032538
dbSNP: rs1173499881
Type: single nucleotide variant
Location: chr6:43263141 (GRCh38)
Gene constraint: LOEUF 0.492 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 52.29 · 17 PDB
Residue 593: the 'disordered' region

Full TTBK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TTBK1 c.331-3C>T Uncertain significance ★★ same type
TTBK1 p.Asn940= Benign/Likely benign ★★ same type
TTBK1 p.Pro613Leu Benign/Likely benign ★★ same type
TTBK1 p.Arg258Gln Likely pathogenic ★ ⚠ same type
TTBK1 p.Ala1083Ser Uncertain significance ★ ⚠ same type
TTBK1 p.Ala1135Thr Uncertain significance ★ ⚠ same type
TTBK1 p.Ala1139Gly Uncertain significance ★ ⚠ same type
TTBK1 p.Ala1151Thr 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/ttbk1-p-val593ile (accessed [today's date]).

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