Is CTSD p.Ile198Val (c.592A>G) pathogenic?

CTSD p.Ile198Val (c.592A>G) is classified Uncertain significance in CTSD (ClinVar, Multiple submitters, 5 submitters; last evaluated 2023-07-17). AlphaMissense: ambiguous (0.5221); Ultra-rare (popmax 0.0416%, amr); Associated with Inborn genetic diseases.

What condition is associated with CTSD p.Ile198Val (c.592A>G)?

CTSD p.Ile198Val (c.592A>G) is associated with Inborn genetic diseases, neuronal ceroid lipofuscinosis 10, neuronal ceroid lipofuscinosis (ClinVar).

How common is CTSD p.Ile198Val (c.592A>G) in the general population?

CTSD p.Ile198Val (c.592A>G) is ultra-rare (popmax 0.0416%, amr) (gnomAD).

What do computational predictors say about CTSD p.Ile198Val (c.592A>G)?

AlphaMissense predicts ambiguous (score 0.5221) — an in-silico prediction, not a clinical call.

CTSD p.Ile198Val

c.592A>G · rs556334193 · VCV527749

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.5221 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0416%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5221	ambiguous
REVEL	0.134	moderately benign-leaning
SaProt	LLR -8.66	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 0.87, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 10 kb · p 0.0029 · regional, not allelic
Overall
CADD	21.8	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 0.0416% Admixed American · 25/60,032 alleles

Filtering AF 0.0289% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0247%

Overall 0.00186% 30/1,614,108 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0416%	2,401
Remaining individualsnot grpmax-eligible	0.008%	12,502

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.Ile198Val
Coding: c.592A>G
MANE Select: NM_001909
dbSNP: rs556334193
Type: single nucleotide variant
Location: chr11:1757436 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.69 · 9 PDB
Residue 198: a β-strand; 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 p.Ile198= Likely benign ★ 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 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

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-ile198val (accessed [today's date]).

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