Is CTSB p.Ser257Trp (c.770C>G) pathogenic?

CTSB p.Ser257Trp (c.770C>G) is classified Uncertain significance in CTSB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-25). AlphaMissense: ambiguous (0.5571); Very rare (popmax 0.00908%, nfe).

How common is CTSB p.Ser257Trp (c.770C>G) in the general population?

CTSB p.Ser257Trp (c.770C>G) is very rare (popmax 0.00908%, nfe) (gnomAD).

What do computational predictors say about CTSB p.Ser257Trp (c.770C>G)?

AlphaMissense predicts ambiguous (score 0.5571) — an in-silico prediction, not a clinical call.

CTSB p.Ser257Trp

c.770C>G · rs147604039 · VCV1521513

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5571 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00908%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5571	ambiguous
REVEL	0.313	indeterminate
SaProt	LLR -13.90	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP -0.73, phastCons 0.84
Regional constraint	o/e 1.73	unconstrained · MANE · 8,326 bp · p 8.5e-54 · regional, not allelic
Overall
CADD	21.8	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 0.00908% European (non-Finnish) · 106/1,167,576 alleles

Filtering AF 0.00765% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00713%

Overall 0.00721% 115/1,595,918 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00908%	11,015
Remaining individualsnot grpmax-eligible	0.00814%	12,289
African / African-American	0.00403%	24,813
Admixed American	0.00168%	59,522

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: CTSB
Protein: p.Ser257Trp
Coding: c.770C>G
MANE Select: NM_001908
dbSNP: rs147604039
Type: single nucleotide variant
Location: chr8:11847075 (GRCh38)
Gene constraint: LOEUF 1.756 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.95 · 21 PDB
Residue 257: an α-helix

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

Similar variants

CTSB p.Ser257Leu Uncertain significance ★ ⚠ same residue
CTSB p.Ser257= Likely benign ★ same residue
CTSB p.Arg331Pro Uncertain significance ★★ ⚠ same type
CTSB p.Asp333Asn Uncertain significance ★★ ⚠ same type
CTSB p.Lys220Glu Uncertain significance ★★ ⚠ same type
CTSB p.Met73Thr Uncertain significance ★★ ⚠ same type
CTSB p.Thr332Ala Uncertain significance ★★ ⚠ same type
CTSB c.327+20C>T Benign ★★ 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/ctsb-p-ser257trp (accessed [today's date]).

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