Is CTSD p.Phe215= (c.645C>T) pathogenic?

CTSD p.Phe215= (c.645C>T) is classified Likely benign in CTSD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-03). Very rare (popmax 0.0011%, sas); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CTSD p.Phe215= (c.645C>T)?

CTSD p.Phe215= (c.645C>T) is associated with neuronal ceroid lipofuscinosis (ClinVar).

How common is CTSD p.Phe215= (c.645C>T) in the general population?

CTSD p.Phe215= (c.645C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

CTSD p.Phe215=

c.645C>T · rs2133661939 · VCV1932946

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.328	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.3	GERP -3.4
Overall
CADD	3.073	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,086 alleles

Overall 0.000205% 3/1,461,794 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,508
South Asiangrpmax	0.0011%	91,086
European (non-Finnish)	8.47e-05%	1,180,043

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe215=
Coding: c.645C>T
MANE Select: NM_001909
dbSNP: rs2133661939
Type: single nucleotide variant
Location: chr11:1757383 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.69 · 9 PDB
Residue 215: 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-phe215 (accessed [today's date]).

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