Is CTSA p.Ser59Phe (c.176C>T) pathogenic?

CTSA p.Ser59Phe (c.176C>T) is classified Uncertain significance in CTSA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-19). AlphaMissense: likely benign (0.218); Very rare (popmax 0.000339%, nfe); Associated with galactosialidosis.

What condition is associated with CTSA p.Ser59Phe (c.176C>T)?

CTSA p.Ser59Phe (c.176C>T) is associated with galactosialidosis (ClinVar).

How common is CTSA p.Ser59Phe (c.176C>T) in the general population?

CTSA p.Ser59Phe (c.176C>T) is very rare (popmax 0.000339%, 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.Ser59Phe (c.176C>T)?

AlphaMissense predicts likely benign (score 0.218) — an in-silico prediction, not a clinical call.

CTSA p.Ser59Phe

c.176C>T · rs774156870 · VCV2149155

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.218 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

galactosialidosis

Computational evidence

Protein change
AlphaMissense	0.218	likely benign
REVEL	0.484	indeterminate
SaProt	LLR -12.41	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.83, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 1,710 bp · p 0.19 · regional, not allelic
Overall
CADD	23.1	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 0.000339% European (non-Finnish) · 4/1,180,044 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,446 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.Ser59Phe
Coding: c.176C>T
MANE Select: NM_000308
dbSNP: rs774156870
Type: single nucleotide variant
Location: chr20:45891744 (GRCh38)
Gene constraint: LOEUF 0.851 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.59 · 12 PDB

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-ser59phe (accessed [today's date]).

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