Is CTSL p.Gln134Arg (c.401A>G) pathogenic?

CTSL p.Gln134Arg (c.401A>G) is classified Uncertain significance in CTSL (ClinVar, Single submitter, 2 submitters; last evaluated 2023-01-23). AlphaMissense: likely benign (0.1303); Ultra-rare (popmax 0.0509%, afr).

How common is CTSL p.Gln134Arg (c.401A>G) in the general population?

CTSL p.Gln134Arg (c.401A>G) is ultra-rare (popmax 0.0509%, afr) (gnomAD).

What do computational predictors say about CTSL p.Gln134Arg (c.401A>G)?

AlphaMissense predicts likely benign (score 0.1303) — an in-silico prediction, not a clinical call.

CTSL p.Gln134Arg

c.401A>G · rs367983711 · VCV2468064

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1303 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0509%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1303	likely benign
REVEL	0.341	indeterminate
SaProt	LLR -9.10	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -3.7
Regional constraint	o/e 0.89	unconstrained · MANE · 3,500 bp · p 0.025 · regional, not allelic
Overall
CADD	9.079	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0509% African / African-American · 38/74,624 alleles

Filtering AF 0.0381% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0336%

Overall 0.00323% 52/1,612,314 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0509%	1,964
Remaining individualsnot grpmax-eligible	0.00961%	10,402
South Asian	0.0044%	22,743
Admixed American	0.00334%	29,919
East Asian	0.00223%	44,846
European (non-Finnish)	8.48e-05%	1,179,199

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.Gln134Arg
Coding: c.401A>G
MANE Select: NM_001912
dbSNP: rs367983711
Type: single nucleotide variant
Location: chr9:87728589 (GRCh38)
Gene constraint: LOEUF 0.932 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.75 · 64 PDB
Residue 134: a β-strand

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

Similar variants

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.Arg153Gln Uncertain significance ★ ⚠ same type
CTSL p.Arg153Trp 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-gln134arg (accessed [today's date]).

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