Is CTSD p.Pro304= (c.912G>A) pathogenic?

CTSD p.Pro304= (c.912G>A) is classified Conflicting classifications of pathogenicity in CTSD (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-05-01). Rare (popmax 0.357%, amr); Associated with Inborn genetic diseases.

What condition is associated with CTSD p.Pro304= (c.912G>A)?

CTSD p.Pro304= (c.912G>A) is associated with Inborn genetic diseases, neuronal ceroid lipofuscinosis 10, neuronal ceroid lipofuscinosis (ClinVar).

How common is CTSD p.Pro304= (c.912G>A) in the general population?

CTSD p.Pro304= (c.912G>A) is rare (popmax 0.357%, amr) (gnomAD).

CTSD p.Pro304=

c.912G>A · rs140238987 · VCV137040

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

gnomAD v4.1

Rare

rare (popmax 0.357%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.018	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -16
Overall
CADD	0.137	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.357% Admixed American · 214/59,926 alleles

Filtering AF 0.318% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.31%

Overall 0.29% 4,676/1,611,174 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.357%	280
Finnishnot grpmax-eligible	0.343%	291
European (non-Finnish)	0.322%	310
Remaining individualsnot grpmax-eligible	0.293%	341
African / African-American	0.24%	417
South Asian	0.0912%	1,096
Middle Eastern	0.0165%	6,056
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,564

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.Pro304=
Coding: c.912G>A
MANE Select: NM_001909
dbSNP: rs140238987
Type: single nucleotide variant
Location: chr11:1754054 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.69 · 9 PDB
Residue 304: the peptidase a1 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neuronal ceroid lipofuscinosis 10 neuronal ceroid lipofuscinosis

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 c.*210C>G Uncertain significance ★★ same condition
CTSD p.Ala10Ser Uncertain significance ★★ ⚠ same condition
CTSD p.Ala116Thr Uncertain significance ★★ ⚠ same condition
CTSD p.Ala18Pro Uncertain significance ★★ ⚠ same condition
CTSD p.Ala18Thr 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-pro304 (accessed [today's date]).

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