Is CTSA p.Leu18fs (c.51_52del) pathogenic?

CTSA p.Leu18fs (c.5152del) is classified Uncertain significance in CTSA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-29). Rare (popmax 0.308%, afr).

How common is CTSA p.Leu18fs (c.51_52del) in the general population?

CTSA p.Leu18fs (c.51_52del) is rare (popmax 0.308%, afr) (gnomAD).

CTSA p.Leu18fs

c.51_52del · rs576896599 · VCV2573389

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.308%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.1	GERP 0.026, phastCons 1
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	(CTG)n simple repeat · ambiguous alignment · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.308% African / African-American · 231/75,020 alleles

Filtering AF 0.275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.263%

Overall 0.0168% 270/1,611,108 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.308%	325
Admixed American	0.0383%	2,609
Remaining individualsnot grpmax-eligible	0.0192%	5,204
Middle Eastern	0.0165%	6,056
Finnishnot grpmax-eligible	0.00163%	61,430
European (non-Finnish)	0.00017%	589,870

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: CTSA
Protein: p.Leu18fs
Coding: c.51_52del
MANE Select: NM_000308
dbSNP: rs576896599
Type: Deletion
Location: chr20:45891619 (GRCh38)
Gene constraint: LOEUF 0.851 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.59 · 12 PDB

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

Similar variants

CTSA p.Leu18_Leu19insTer Pathogenic ★ same residue
CTSA p.Leu18_Leu19del Benign/Likely benign ★★ same residue
CTSA p.Leu18_Leu19dup Uncertain significance ★ same residue
CTSA p.Leu18Arg Uncertain significance ★ ⚠ same residue
CTSA p.Leu18= Likely benign ★ same residue
CTSA c.445-18_447del Likely pathogenic ★★ same type
CTSA p.Ala336fs Pathogenic/Likely pathogenic ★★ same type
CTSA p.Arg48fs Pathogenic ★★ 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/ctsa-p-leu18fs (accessed [today's date]).

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