Is CTSL p.Arg153Trp (c.457C>T) pathogenic?

CTSL p.Arg153Trp (c.457C>T) is classified Uncertain significance in CTSL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-12). AlphaMissense: likely benign (0.2482); Very rare (popmax 0.00659%, sas).

How common is CTSL p.Arg153Trp (c.457C>T) in the general population?

CTSL p.Arg153Trp (c.457C>T) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about CTSL p.Arg153Trp (c.457C>T)?

AlphaMissense predicts likely benign (score 0.2482) — an in-silico prediction, not a clinical call.

CTSL p.Arg153Trp

c.457C>T · rs775710216 · VCV2611567

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2482 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2482	likely benign
REVEL	0.139	moderately benign-leaning
SaProt	LLR -13.71	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -12	GERP 1.7
Regional constraint	o/e 0.89	unconstrained · MANE · 3,500 bp · p 0.025 · regional, not allelic
Overall
CADD	22.9	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 0.00659% South Asian · 6/91,070 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00149% 24/1,613,838 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,178
African / African-American	0.00401%	24,943
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
Admixed American	0.00167%	59,986
Remaining individualsnot grpmax-eligible	0.0016%	62,476
European (non-Finnish)	0.00102%	98,334

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: CTSL
Protein: p.Arg153Trp
Coding: c.457C>T
MANE Select: NM_001912
dbSNP: rs775710216
Type: single nucleotide variant
Location: chr9:87728645 (GRCh38)
Gene constraint: LOEUF 0.932 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.75 · 64 PDB
Residue 153: a disulfide bond; an α-helix

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

Similar variants

CTSL p.Arg153Gln Uncertain significance ★ ⚠ same residue
CTSL p.Thr207Ile Uncertain significance ★★ ⚠ same type
CTSL p.Ser117Tyr Benign ★★ ⚠ same type
CTSL p.Ala143Thr Uncertain significance ★ ⚠ same type
CTSL p.Ala15Val Uncertain significance ★ ⚠ same type
CTSL p.Ala220Gly Uncertain significance ★ ⚠ same type
CTSL p.Ala50Gly Uncertain significance ★ ⚠ same type
CTSL p.Arg318Trp 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/ctsl-p-arg153trp (accessed [today's date]).

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