Is CTSD p.Lys331Asn (c.993G>C) pathogenic?

CTSD p.Lys331Asn (c.993G>C) is classified Uncertain significance in CTSD (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely benign (0.2995); Absent from gnomAD v4.1; Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CTSD p.Lys331Asn (c.993G>C)?

CTSD p.Lys331Asn (c.993G>C) is associated with neuronal ceroid lipofuscinosis (ClinVar).

How common is CTSD p.Lys331Asn (c.993G>C) in the general population?

CTSD p.Lys331Asn (c.993G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CTSD p.Lys331Asn (c.993G>C)?

AlphaMissense predicts likely benign (score 0.2995) — an in-silico prediction, not a clinical call.

CTSD p.Lys331Asn

c.993G>C · rs1181418072 · VCV527731

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2995 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
AlphaMissense	0.2995	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -8.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 10 kb · p 0.0029 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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.Lys331Asn
Coding: c.993G>C
MANE Select: NM_001909
dbSNP: rs1181418072
Type: single nucleotide variant
Location: chr11:1753881 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.69 · 9 PDB
Residue 331: a disulfide bond; the peptidase a1 domain; an α-helix

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.Lys331= 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-lys331asn (accessed [today's date]).

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