Is CTSA p.Pro329Ala (c.985C>G) pathogenic?

CTSA p.Pro329Ala (c.985C>G) is classified Conflicting classifications of pathogenicity in CTSA (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-22). AlphaMissense: likely benign (0.3252); Ultra-rare (popmax 0.0317%, amr); Associated with Inborn genetic diseases.

What condition is associated with CTSA p.Pro329Ala (c.985C>G)?

CTSA p.Pro329Ala (c.985C>G) is associated with Inborn genetic diseases, galactosialidosis (ClinVar).

How common is CTSA p.Pro329Ala (c.985C>G) in the general population?

CTSA p.Pro329Ala (c.985C>G) is ultra-rare (popmax 0.0317%, amr) (gnomAD).

What do computational predictors say about CTSA p.Pro329Ala (c.985C>G)?

AlphaMissense predicts likely benign (score 0.3252) — an in-silico prediction, not a clinical call.

CTSA p.Pro329Ala

c.985C>G · rs746428492 · VCV1407441

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3252 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0317%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3252	likely benign
REVEL	0.753	pathogenic-leaning
SaProt	LLR -6.78	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 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 4,432 bp · p 0.0086 · regional, not allelic
Overall
CADD	25.4	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 0.0317% Admixed American · 19/59,978 alleles

Filtering AF 0.0207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.00149% 24/1,613,970 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0317%	3,157
Remaining individualsnot grpmax-eligible	0.0016%	62,482
African / African-American	0.00134%	74,904
European (non-Finnish)	0.000254%	393,338

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.Pro329Ala
Coding: c.985C>G
MANE Select: NM_000308
dbSNP: rs746428492
Type: single nucleotide variant
Location: chr20:45895030 (GRCh38)
Gene constraint: LOEUF 0.851 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.59 · 12 PDB
Residue 329: a disulfide bond

Full CTSA 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: galactosialidosis

Similar variants

CTSA p.Pro329Thr Uncertain significance ★★ ⚠ same residue
CTSA p.Pro329= Likely benign ★ 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

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-pro329ala (accessed [today's date]).

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