Is CTSA p.Leu187Val (c.559C>G) pathogenic?

CTSA p.Leu187Val (c.559C>G) is classified Uncertain significance in CTSA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-24). AlphaMissense: ambiguous (0.3589); Very rare (popmax 0.000424%, nfe); Associated with galactosialidosis.

What condition is associated with CTSA p.Leu187Val (c.559C>G)?

CTSA p.Leu187Val (c.559C>G) is associated with galactosialidosis (ClinVar).

How common is CTSA p.Leu187Val (c.559C>G) in the general population?

CTSA p.Leu187Val (c.559C>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

How is Galactosialidosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CTSA p.Leu187Val (c.559C>G)?

AlphaMissense predicts ambiguous (score 0.3589) — an in-silico prediction, not a clinical call.

CTSA p.Leu187Val

c.559C>G · VCV3705763

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3589 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

galactosialidosis

Computational evidence

Protein change
AlphaMissense	0.3589	ambiguous
REVEL	0.774	moderately pathogenic-leaning
SaProt	LLR -10.46	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -0.53, phastCons 0.99
Regional constraint	o/e 0.92	unconstrained · MANE · 1,710 bp · p 0.19 · regional, not allelic
Overall
CADD	23.4	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 0.000424% European (non-Finnish) · 5/1,180,038 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,614,204 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,512
European (non-Finnish)grpmax	0.000424%	236,008

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: CTSA
Protein: p.Leu187Val
Coding: c.559C>G
MANE Select: NM_000308
Type: single nucleotide variant
Location: chr20:45892839 (GRCh38)
Gene constraint: LOEUF 0.851 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.59 · 12 PDB
Residue 187: an α-helix; a disulfide bond

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

Disease context

galactosialidosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Galactosialidosis (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages

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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/ctsa-p-leu187val (accessed [today's date]).

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