Is CTSA p.Arg326His (c.977G>A) pathogenic?

CTSA p.Arg326His (c.977G>A) is classified Uncertain significance in CTSA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-06). AlphaMissense: likely benign (0.1311); Ultra-rare (popmax 0.0301%, nfe); Associated with galactosialidosis.

What condition is associated with CTSA p.Arg326His (c.977G>A)?

CTSA p.Arg326His (c.977G>A) is associated with galactosialidosis (ClinVar).

How common is CTSA p.Arg326His (c.977G>A) in the general population?

CTSA p.Arg326His (c.977G>A) is ultra-rare (popmax 0.0301%, 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.Arg326His (c.977G>A)?

AlphaMissense predicts likely benign (score 0.1311) — an in-silico prediction, not a clinical call.

CTSA p.Arg326His

c.977G>A · rs554534522 · VCV841568

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1311 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0301%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

galactosialidosis

Computational evidence

Protein change
AlphaMissense	0.1311	likely benign
REVEL	0.205	benign-leaning
SaProt	LLR -3.65	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP -2.3, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 4,432 bp · p 0.0086 · regional, not allelic
Overall
CADD	16.44	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0301% European (non-Finnish) · 355/1,180,026 alleles

Filtering AF 0.0275% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0265%

Overall 0.024% 387/1,614,008 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0301%	3,324
Remaining individualsnot grpmax-eligible	0.0224%	4,463
East Asian	0.02%	4,988
Admixed American	0.00833%	11,998
African / African-American	0.00267%	37,452
South Asian	0.0022%	45,547

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.Arg326His
Coding: c.977G>A
MANE Select: NM_000308
dbSNP: rs554534522
Type: single nucleotide variant
Location: chr20:45895022 (GRCh38)
Gene constraint: LOEUF 0.851 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.59 · 12 PDB
Residue 326: a disulfide bond; a β-strand

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

Similar variants

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
CTSA p.Cys281Ter 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-arg326his (accessed [today's date]).

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