Is CTSD p.Ser56Pro (c.166T>C) pathogenic?

CTSD p.Ser56Pro (c.166T>C) is classified Uncertain significance in CTSD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-04). AlphaMissense: likely benign (0.1571); Very rare (popmax 0.000169%, nfe); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CTSD p.Ser56Pro (c.166T>C)?

CTSD p.Ser56Pro (c.166T>C) is associated with neuronal ceroid lipofuscinosis (ClinVar).

How common is CTSD p.Ser56Pro (c.166T>C) in the general population?

CTSD p.Ser56Pro (c.166T>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about CTSD p.Ser56Pro (c.166T>C)?

AlphaMissense predicts likely benign (score 0.1571) — an in-silico prediction, not a clinical call.

CTSD p.Ser56Pro

c.166T>C · rs2493829786 · VCV2090484

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1571 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
AlphaMissense	0.1571	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -7.69	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -1.4	GERP -2
Regional constraint	o/e 0.87	unconstrained · MANE · 10 kb · p 0.0029 · regional, not allelic
Overall
CADD	3.404	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 0.000169% European (non-Finnish) · 2/1,179,990 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000205% 3/1,461,464 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,500
European (non-Finnish)grpmax	0.000169%	589,995

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.Ser56Pro
Coding: c.166T>C
dbSNP: rs2493829786
Type: single nucleotide variant
Location: chr11:1761371 (GRCh38)

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

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-ser56pro (accessed [today's date]).

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