Is CTSB p.Ser235Asn (c.704G>A) pathogenic?

CTSB p.Ser235Asn (c.704G>A) is classified Benign in CTSB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-23). AlphaMissense: likely benign (0.0827); Common (popmax 14.5%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about CTSB p.Ser235Asn (c.704G>A)?

AlphaMissense predicts likely benign (score 0.0827) — an in-silico prediction, not a clinical call.

CTSB p.Ser235Asn

Q: How common is CTSB p.Ser235Asn (c.704G>A) in the general population?

CTSB p.Ser235Asn (c.704G>A) is common (popmax 14.5%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.704G>A · rs17573 · VCV1167517

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0827 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 14.5%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0827	likely benign
REVEL	0.164	moderately benign-leaning
SaProt	LLR -7.10	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 -5.2	GERP -3.4
Regional constraint	o/e 1.73	unconstrained · MANE · 8,326 bp · p 8.5e-54 · regional, not allelic
Overall
CADD	0.002	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 14.5% African / African-American · 10,314/71,118 alleles

Filtering AF 14.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 14.2%

Overall 0.793% 12,638/1,593,386 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	14.5%	7
Admixed American	1.12%	90
Remaining individualsnot grpmax-eligible	1.04%	96
Middle Eastern	0.905%	111
Ashkenazi Jewishnot grpmax-eligible	0.268%	373
South Asian	0.0759%	1,317
European (non-Finnish)	0.0705%	1,419
Finnishnot grpmax-eligible	0.00633%	15,799
East Asian	0.00454%	22,010

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.Ser235Asn
Coding: c.704G>A
MANE Select: NM_001908
dbSNP: rs17573
Type: single nucleotide variant
Location: chr8:11847141 (GRCh38)
Gene constraint: LOEUF 1.756 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.95 · 21 PDB
Residue 235: a UniProt-annotated variant site (in)

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

Similar variants

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
CTSB c.446+9G>C Benign ★★ same type
CTSB c.447-16G>C 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-ser235asn (accessed [today's date]).

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