Is CTSD p.Arg33His (c.98G>A) pathogenic?

CTSD p.Arg33His (c.98G>A) is classified Uncertain significance in CTSD (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-15). AlphaMissense: likely pathogenic (0.6619); Very rare (popmax 0.00439%, sas); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CTSD p.Arg33His (c.98G>A)?

CTSD p.Arg33His (c.98G>A) is associated with neuronal ceroid lipofuscinosis (ClinVar).

How common is CTSD p.Arg33His (c.98G>A) in the general population?

CTSD p.Arg33His (c.98G>A) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about CTSD p.Arg33His (c.98G>A)?

AlphaMissense predicts likely pathogenic (score 0.6619) — an in-silico prediction, not a clinical call.

CTSD p.Arg33His

c.98G>A · rs557024887 · VCV2048121

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6619 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
AlphaMissense	0.6619	likely pathogenic
REVEL	0.723	pathogenic-leaning
SaProt	LLR -9.42	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.4	GERP 1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 10 kb · p 0.0029 · regional, not allelic
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00439% South Asian · 4/91,082 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000806% 13/1,613,888 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,770
East Asian	0.00223%	44,882
European (non-Finnish)	0.000678%	147,500

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.Arg33His
Coding: c.98G>A
dbSNP: rs557024887
Type: single nucleotide variant
Location: chr11:1761439 (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-arg33his (accessed [today's date]).

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