Is CTSD p.Gly257= (c.771T>C) pathogenic?

CTSD p.Gly257= (c.771T>C) is classified Likely benign in CTSD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-27). Very rare (popmax 0.00535%, afr); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CTSD p.Gly257= (c.771T>C)?

CTSD p.Gly257= (c.771T>C) is associated with neuronal ceroid lipofuscinosis (ClinVar).

How common is CTSD p.Gly257= (c.771T>C) in the general population?

CTSD p.Gly257= (c.771T>C) is very rare (popmax 0.00535%, afr) (gnomAD).

CTSD p.Gly257=

c.771T>C · rs376607594 · VCV1139723

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00535%, afr)

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.009	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.92	GERP -3.7
Overall
CADD	4.292	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00535% African / African-American · 4/74,832 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000372% 6/1,613,742 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00535%	18,708
South Asian	0.0022%	45,542

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.Gly257=
Coding: c.771T>C
MANE Select: NM_001909
dbSNP: rs376607594
Type: single nucleotide variant
Location: chr11:1754962 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.69 · 9 PDB
Residue 257: a β-strand; 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 p.Gly257Ser Uncertain significance ★★ ⚠ same residue
CTSD p.Gly257Ala Uncertain significance ★ ⚠ 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

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-gly257 (accessed [today's date]).

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