Is CTSD p.Asp216Asn (c.646G>A) pathogenic?

CTSD p.Asp216Asn (c.646G>A) is classified Uncertain significance in CTSD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-19). AlphaMissense: likely pathogenic (0.8435); Very rare (popmax 0.00167%, amr); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CTSD p.Asp216Asn (c.646G>A)?

CTSD p.Asp216Asn (c.646G>A) is associated with neuronal ceroid lipofuscinosis (ClinVar).

How common is CTSD p.Asp216Asn (c.646G>A) in the general population?

CTSD p.Asp216Asn (c.646G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CTSD p.Asp216Asn (c.646G>A)?

AlphaMissense predicts likely pathogenic (score 0.8435) — an in-silico prediction, not a clinical call.

CTSD p.Asp216Asn

c.646G>A · rs1235872591 · VCV967445

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8435 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
AlphaMissense	0.8435	likely pathogenic
REVEL	0.432	indeterminate
SaProt	LLR -10.13	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP -0.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 10 kb · p 0.0029 · regional, not allelic
Overall
CADD	27.0	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

Grpmax group 0.00167% Admixed American · 1/60,024 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,461,774 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,024
European (non-Finnish)	0.000254%	393,345

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.Asp216Asn
Coding: c.646G>A
MANE Select: NM_001909
dbSNP: rs1235872591
Type: single nucleotide variant
Location: chr11:1757382 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.69 · 9 PDB
Residue 216: 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 — 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-asp216asn (accessed [today's date]).

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