Is CTSL p.Arg153Gln (c.458G>A) pathogenic?

CTSL p.Arg153Gln (c.458G>A) is classified Uncertain significance in CTSL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-02). AlphaMissense: likely benign (0.112); Ultra-rare (popmax 0.033%, mid).

How common is CTSL p.Arg153Gln (c.458G>A) in the general population?

CTSL p.Arg153Gln (c.458G>A) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about CTSL p.Arg153Gln (c.458G>A)?

AlphaMissense predicts likely benign (score 0.112) — an in-silico prediction, not a clinical call.

CTSL p.Arg153Gln

c.458G>A · rs201186758 · VCV2342541

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.112 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.112	likely benign
REVEL	0.075	moderately benign-leaning
SaProt	LLR -10.27	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 -4.8	GERP -1.5
Regional constraint	o/e 0.89	unconstrained · MANE · 3,500 bp · p 0.025 · regional, not allelic
Overall
CADD	21.2	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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.0044% 71/1,614,032 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
South Asian	0.0121%	8,279
East Asian	0.00669%	14,953
Admixed American	0.005%	19,996
Remaining individualsnot grpmax-eligible	0.0048%	20,836
European (non-Finnish)	0.00398%	25,107
African / African-American	0.00267%	37,489

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.Arg153Gln
Coding: c.458G>A
MANE Select: NM_001912
dbSNP: rs201186758
Type: single nucleotide variant
Location: chr9:87728646 (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.Arg153Trp 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-arg153gln (accessed [today's date]).

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