Is TTK p.Ser148Cys (c.443C>G) pathogenic?

TTK p.Ser148Cys (c.443C>G) is classified Uncertain significance in TTK (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-02). AlphaMissense: likely benign (0.1021); Rare (popmax 0.198%, afr).

How common is TTK p.Ser148Cys (c.443C>G) in the general population?

TTK p.Ser148Cys (c.443C>G) is rare (popmax 0.198%, afr) (gnomAD).

What do computational predictors say about TTK p.Ser148Cys (c.443C>G)?

AlphaMissense predicts likely benign (score 0.1021) — an in-silico prediction, not a clinical call.

TTK p.Ser148Cys

c.443C>G · rs145266061 · VCV3184501

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1021 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.198%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1021	likely benign
REVEL	0.257	benign-leaning
SaProt	LLR -7.84	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 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 36 kb · p 0.03 · regional, not allelic
Overall
CADD	25.7	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 0.198% African / African-American · 148/74,926 alleles

Filtering AF 0.172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.162%

Overall 0.00956% 154/1,611,624 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.198%	506
Admixed American	0.00502%	19,920
Remaining individualsnot grpmax-eligible	0.00321%	31,200
European (non-Finnish)	8.48e-05%	1,178,842

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.Ser148Cys
Coding: c.443C>G
MANE Select: NM_003318
dbSNP: rs145266061
Type: single nucleotide variant
Location: chr6:80008466 (GRCh38)
Gene constraint: LOEUF 0.666 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.11 · 78 PDB
Residue 148: 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-ser148cys (accessed [today's date]).

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