Is CTSD p.Thr355Met (c.1064C>T) pathogenic?

CTSD p.Thr355Met (c.1064C>T) is classified Uncertain significance in CTSD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-29). AlphaMissense: likely benign (0.183); Ultra-rare (popmax 0.0165%, mid); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CTSD p.Thr355Met (c.1064C>T)?

CTSD p.Thr355Met (c.1064C>T) is associated with neuronal ceroid lipofuscinosis (ClinVar).

How common is CTSD p.Thr355Met (c.1064C>T) in the general population?

CTSD p.Thr355Met (c.1064C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CTSD p.Thr355Met (c.1064C>T)?

AlphaMissense predicts likely benign (score 0.183) — an in-silico prediction, not a clinical call.

CTSD p.Thr355Met

c.1064C>T · rs1318388119 · VCV2150593

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.183 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
AlphaMissense	0.183	likely benign
REVEL	0.169	moderately benign-leaning
SaProt	LLR -11.43	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 3.2	phastCons 0.11
Regional constraint	o/e 0.87	unconstrained · MANE · 10 kb · p 0.0029 · 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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,522 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
European (non-Finnish)	0.00017%	589,877

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.Thr355Met
Coding: c.1064C>T
MANE Select: NM_001909
dbSNP: rs1318388119
Type: single nucleotide variant
Location: chr11:1753810 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.69 · 9 PDB
Residue 355: a disulfide bond; the peptidase a1 domain; a β-strand

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 p.Thr355= Likely benign ★★ same residue
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

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-thr355met (accessed [today's date]).

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