Is CTSD p.Gln220Pro (c.659A>C) pathogenic?

CTSD p.Gln220Pro (c.659A>C) is classified Uncertain significance in CTSD (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: likely pathogenic (0.7792); Absent from gnomAD v4.1; Associated with neuronal ceroid lipofuscinosis 10.

What condition is associated with CTSD p.Gln220Pro (c.659A>C)?

CTSD p.Gln220Pro (c.659A>C) is associated with neuronal ceroid lipofuscinosis 10 (ClinVar).

How common is CTSD p.Gln220Pro (c.659A>C) in the general population?

CTSD p.Gln220Pro (c.659A>C) is absent from gnomAD v4.1 (gnomAD).

How is CLN10 disease inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CTSD p.Gln220Pro (c.659A>C)?

AlphaMissense predicts likely pathogenic (score 0.7792) — an in-silico prediction, not a clinical call.

CTSD p.Gln220Pro

c.659A>C · rs886048066 · VCV303839

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7792 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis 10

Computational evidence

Protein change
AlphaMissense	0.7792	likely pathogenic
REVEL	0.194	benign-leaning
SaProt	LLR -13.74	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.69	GERP -0.53
Regional constraint	o/e 0.87	unconstrained · MANE · 10 kb · p 0.0029 · regional, not allelic
Overall
CADD	18.01	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

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.Gln220Pro
Coding: c.659A>C
MANE Select: NM_001909
dbSNP: rs886048066
Type: single nucleotide variant
Location: chr11:1757369 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.69 · 9 PDB
Residue 220: an α-helix; the peptidase a1 domain

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

Disease context

neuronal ceroid lipofuscinosis 10 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CLN10 disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult, Antenatal, Infancy

Similar variants

CTSD p.Gln220His Uncertain significance ★ ⚠ same residue
CTSD p.Gln220Ter Pathogenic ★ same residue
CTSD c.*210C>G Uncertain significance ★★ same condition
CTSD p.Ala239Val Uncertain significance ★★ ⚠ same condition
CTSD p.Arg411His Uncertain significance ★★ ⚠ same condition
CTSD p.Glu310Lys Uncertain significance ★★ ⚠ same condition
CTSD p.Gly316Arg Uncertain significance ★★ ⚠ same condition
CTSD p.Gly362Arg 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-gln220pro (accessed [today's date]).

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