Is CTSD p.Glu64Asp (c.192G>C) pathogenic?

CTSD p.Glu64Asp (c.192G>C) is classified Uncertain significance in CTSD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-07). AlphaMissense: likely benign (0.0781); Very rare (popmax 0.000254%, nfe).

How common is CTSD p.Glu64Asp (c.192G>C) in the general population?

CTSD p.Glu64Asp (c.192G>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CTSD p.Glu64Asp (c.192G>C)?

AlphaMissense predicts likely benign (score 0.0781) — an in-silico prediction, not a clinical call.

CTSD p.Glu64Asp

c.192G>C · VCV4527495

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0781 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0781	likely benign
REVEL	0.055	moderately benign-leaning
SaProt	LLR -5.52	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 -2.2	GERP -2
Regional constraint	o/e 0.87	unconstrained · MANE · 10 kb · p 0.0029 · regional, not allelic
Overall
CADD	3.371	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

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,020 alleles

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

Overall 0.000205% 3/1,461,582 alleles · very rare

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.Glu64Asp
Coding: c.192G>C
MANE Select: NM_001909
Type: single nucleotide variant
Location: chr11:1761345 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.69 · 9 PDB

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

Similar variants

CTSD p.Glu64Ter Pathogenic ★ same residue
CTSD p.Glu64Gln Uncertain significance ★ ⚠ same residue
CTSD p.Glu64Lys Uncertain significance ★ ⚠ same residue
CTSD c.228+1G>A Likely pathogenic ★★ same type
CTSD p.Glu82Ter Pathogenic/Likely pathogenic ★★ same type
CTSD c.828-3C>A Uncertain significance ★★ same type
CTSD c.*210C>G Uncertain significance ★★ same type
CTSD p.Ala10Ser Uncertain significance ★★ ⚠ same type

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-glu64asp (accessed [today's date]).

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