Is CTSD p.Leu233= (c.697C>T) pathogenic?

CTSD p.Leu233= (c.697C>T) is classified Conflicting classifications of pathogenicity in CTSD (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-26). Ultra-rare (popmax 0.0866%, afr); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CTSD p.Leu233= (c.697C>T)?

CTSD p.Leu233= (c.697C>T) is associated with neuronal ceroid lipofuscinosis (ClinVar).

How common is CTSD p.Leu233= (c.697C>T) in the general population?

CTSD p.Leu233= (c.697C>T) is ultra-rare (popmax 0.0866%, afr) (gnomAD).

CTSD p.Leu233=

c.697C>T · rs142330967 · VCV700124

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0866%, afr)

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.62 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.3	GERP -2.1, phastCons 1
Overall
CADD	9.666	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0866% African / African-American · 65/75,060 alleles

Filtering AF 0.0697% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0635%

Overall 0.00465% 75/1,613,426 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0866%	1,155
Remaining individualsnot grpmax-eligible	0.0112%	8,927
South Asian	0.0011%	91,044
European (non-Finnish)	0.00017%	589,824

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: CTSD
Protein: p.Leu233=
Coding: c.697C>T
MANE Select: NM_001909
dbSNP: rs142330967
Type: single nucleotide variant
Location: chr11:1757331 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.69 · 9 PDB
Residue 233: a β-strand; the peptidase a1 domain

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

Disease context

neuronal ceroid lipofuscinosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CTSD c.228+1G>A Likely pathogenic ★★ same condition
CTSD p.Glu82Ter Pathogenic/Likely pathogenic ★★ same condition
CTSD c.828-3C>A Uncertain significance ★★ same condition
CTSD p.Ala10Ser Uncertain significance ★★ ⚠ same condition
CTSD p.Ala18Pro Uncertain significance ★★ ⚠ same condition
CTSD p.Ala18Thr Uncertain significance ★★ ⚠ same condition
CTSD p.Ala239Val Uncertain significance ★★ ⚠ same condition
CTSD p.Arg176Lys Uncertain significance ★★ ⚠ same condition

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/ctsd-p-leu233 (accessed [today's date]).

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