Is CTSB p.Ser53Gly (c.157A>G) pathogenic?

CTSB p.Ser53Gly (c.157A>G) is classified Benign in CTSB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.0896); Common (popmax 14.4%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with keratolytic winter erythema.

What condition is associated with CTSB p.Ser53Gly (c.157A>G)?

CTSB p.Ser53Gly (c.157A>G) is associated with keratolytic winter erythema (ClinVar).

How is Keratolytic winter erythema inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CTSB p.Ser53Gly (c.157A>G)?

AlphaMissense predicts likely benign (score 0.0896) — an in-silico prediction, not a clinical call.

CTSB p.Ser53Gly

Q: How common is CTSB p.Ser53Gly (c.157A>G) in the general population?

CTSB p.Ser53Gly (c.157A>G) is common (popmax 14.4%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.157A>G · rs1803250 · VCV1098730

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0896 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 14.4%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

keratolytic winter erythema

Computational evidence

Protein change
AlphaMissense	0.0896	likely benign
REVEL	0.105	moderately benign-leaning
SaProt	LLR -6.32	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	GERP 0.79, phastCons 1
Regional constraint	o/e 1.73	unconstrained · MANE · 8,326 bp · p 8.5e-54 · regional, not allelic
Overall
CADD	20.5	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 14.4% European (non-Finnish) · 170,211/1,179,542 alleles

Filtering AF 14.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 14.3%

Overall 12.4% 199,472/1,613,452 alleles · common

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	14.4%	7
Middle Eastern	12.3%	8
Remaining individualsnot grpmax-eligible	11.8%	8
Amishnot grpmax-eligible	10.8%	9
Ashkenazi Jewishnot grpmax-eligible	9.81%	10
Finnishnot grpmax-eligible	9.33%	11
Admixed American	7.12%	14
South Asian	4.79%	21
African / African-American	4.7%	21
East Asian	0.0267%	3,739

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.Ser53Gly
Coding: c.157A>G
MANE Select: NM_001908
dbSNP: rs1803250
Type: single nucleotide variant
Location: chr8:11852665 (GRCh38)
Gene constraint: LOEUF 1.756 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 91.95 · 21 PDB
Residue 53: a UniProt-annotated variant site (in); an α-helix

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

Disease context

keratolytic winter erythema — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Keratolytic winter erythema (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Infancy, Neonatal

Similar variants

CTSB c.533-11C>G Benign ★★ same condition
CTSB c.127-11CT[2] Conflicting classifications of pathogenicity ★ same condition
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-ser53gly (accessed [today's date]).

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