Is CTSA p.Arg307Cys (c.919C>T) pathogenic?

CTSA p.Arg307Cys (c.919C>T) is classified Conflicting classifications of pathogenicity in CTSA (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.2536); Very rare (popmax 8.47e-05%, nfe); Associated with CTSA-related disorder.

What condition is associated with CTSA p.Arg307Cys (c.919C>T)?

CTSA p.Arg307Cys (c.919C>T) is associated with CTSA-related disorder, galactosialidosis, brain small vessel disease 6 with leukoencephalopathy (ClinVar).

How common is CTSA p.Arg307Cys (c.919C>T) in the general population?

CTSA p.Arg307Cys (c.919C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CTSA p.Arg307Cys (c.919C>T)?

AlphaMissense predicts likely benign (score 0.2536) — an in-silico prediction, not a clinical call.

CTSA p.Arg307Cys

c.919C>T · rs2145819152 · VCV1373295

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2536 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CTSA-related disorder

Computational evidence

Protein change
AlphaMissense	0.2536	likely benign
REVEL	0.665	pathogenic-leaning
SaProt	LLR -8.10	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 0.55, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 4,432 bp · p 0.0086 · regional, not allelic
Overall
CADD	24.2	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 8.47e-05% European (non-Finnish) · 1/1,180,030 alleles

Overall 6.84e-05% 1/1,461,886 alleles · very rare

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.Arg307Cys
Coding: c.919C>T
MANE Select: NM_000308
dbSNP: rs2145819152
Type: single nucleotide variant
Location: chr20:45894872 (GRCh38)
Gene constraint: LOEUF 0.851 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.59 · 12 PDB
Residue 307: a disulfide bond; a UniProt-annotated variant site (in bsvd6; likely pathogenic)

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

Disease context

CTSA-related disorder

Also linked: galactosialidosis brain small vessel disease 6 with leukoencephalopathy

Similar variants

CTSA p.Arg307His Uncertain significance ★★ ⚠ same residue
CTSA c.1-2A>G Pathogenic/Likely pathogenic ★★ same condition
CTSA c.358-2A>G Likely pathogenic ★★ same condition
CTSA c.601-2A>G Pathogenic/Likely pathogenic ★★ same condition
CTSA c.692+3A>G Pathogenic ★★ same condition
CTSA c.948+1G>A Likely pathogenic ★★ same condition
CTSA p.Arg375Ter Pathogenic/Likely pathogenic ★★ same condition
CTSA p.Cys256Ter Pathogenic/Likely pathogenic ★★ 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/ctsa-p-arg307cys (accessed [today's date]).

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