Is CTSA p.Val346Met (c.1036G>A) pathogenic?

CTSA p.Val346Met (c.1036G>A) is classified Conflicting classifications of pathogenicity in CTSA (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-02-02). AlphaMissense: likely pathogenic (0.6917); Rare (popmax 0.223%, eas); Associated with galactosialidosis.

What condition is associated with CTSA p.Val346Met (c.1036G>A)?

CTSA p.Val346Met (c.1036G>A) is associated with galactosialidosis (ClinVar).

How common is CTSA p.Val346Met (c.1036G>A) in the general population?

CTSA p.Val346Met (c.1036G>A) is rare (popmax 0.223%, eas) (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.Val346Met (c.1036G>A)?

AlphaMissense predicts likely pathogenic (score 0.6917) — an in-silico prediction, not a clinical call.

CTSA p.Val346Met

c.1036G>A · rs137941635 · VCV338536

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6917 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

galactosialidosis

Computational evidence

Protein change
AlphaMissense	0.6917	likely pathogenic
REVEL	0.812	moderately pathogenic-leaning
SaProt	LLR -14.48	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.8, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 4,432 bp · p 0.0086 · regional, not allelic
Overall
CADD	26.6	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 0.223% East Asian · 100/44,882 alleles

Filtering AF 0.187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.174%

Overall 0.00799% 129/1,614,150 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.223%	449
Middle Eastern	0.0165%	6,062
African / African-American	0.0107%	9,380
Remaining individualsnot grpmax-eligible	0.008%	12,502
Admixed American	0.005%	20,002
South Asian	0.0022%	45,543
European (non-Finnish)	0.000847%	118,003

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.Val346Met
Coding: c.1036G>A
MANE Select: NM_000308
dbSNP: rs137941635
Type: single nucleotide variant
Location: chr20:45895081 (GRCh38)
Gene constraint: LOEUF 0.851 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.59 · 12 PDB
Residue 346: 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

Similar variants

CTSA p.Val346= 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
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-val346met (accessed [today's date]).

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