Is CTSD p.Thr296Arg (c.887C>G) pathogenic?

CTSD p.Thr296Arg (c.887C>G) is classified Uncertain significance in CTSD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-22). AlphaMissense: likely pathogenic (0.9942); Absent from gnomAD v4.1; Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CTSD p.Thr296Arg (c.887C>G)?

CTSD p.Thr296Arg (c.887C>G) is associated with neuronal ceroid lipofuscinosis (ClinVar).

How common is CTSD p.Thr296Arg (c.887C>G) in the general population?

CTSD p.Thr296Arg (c.887C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CTSD p.Thr296Arg (c.887C>G)?

AlphaMissense predicts likely pathogenic (score 0.9942) — an in-silico prediction, not a clinical call.

CTSD p.Thr296Arg

c.887C>G · rs2493817064 · VCV2113360

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9942 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
AlphaMissense	0.9942	likely pathogenic · top 7% in CTSD
REVEL	0.856	moderately pathogenic-leaning
SaProt	LLR -14.92	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 10 kb · p 0.0029 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CTSD
Protein: p.Thr296Arg
Coding: c.887C>G
MANE Select: NM_001909
dbSNP: rs2493817064
Type: single nucleotide variant
Location: chr11:1754079 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.69 · 9 PDB
Residue 296: 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 p.Thr296= 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-thr296arg (accessed [today's date]).

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