Is CTSW p.Pro358Leu (c.1073C>T) pathogenic?

CTSW p.Pro358Leu (c.1073C>T) is classified Uncertain significance in CTSW (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-02). AlphaMissense: likely pathogenic (0.6293); Very rare (popmax 0.00267%, afr).

How common is CTSW p.Pro358Leu (c.1073C>T) in the general population?

CTSW p.Pro358Leu (c.1073C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CTSW p.Pro358Leu (c.1073C>T)?

AlphaMissense predicts likely pathogenic (score 0.6293) — an in-silico prediction, not a clinical call.

CTSW p.Pro358Leu

c.1073C>T · rs768538496 · VCV3078795

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6293 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6293	likely pathogenic
REVEL	0.262	benign-leaning
SaProt	LLR -9.44	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 3,760 bp · p 0.82 · regional, not allelic
Overall
CADD	24.1	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 0.00267% African / African-American · 2/74,898 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000929% 15/1,613,990 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,449
East Asian	0.00223%	44,896
South Asian	0.0011%	91,090
European (non-Finnish)	0.000932%	107,271

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: CTSW
Protein: p.Pro358Leu
Coding: c.1073C>T
MANE Select: NM_001335
dbSNP: rs768538496
Type: single nucleotide variant
Location: chr11:65883560 (GRCh38)
Gene constraint: LOEUF 1.135 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.28

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

Similar variants

CTSW p.Ala109Gly Uncertain significance ★ ⚠ same type
CTSW p.Ala140Thr Uncertain significance ★ ⚠ same type
CTSW p.Ala28Val Uncertain significance ★ ⚠ same type
CTSW p.Ala41Asp Uncertain significance ★ ⚠ same type
CTSW p.Ala41Thr Uncertain significance ★ ⚠ same type
CTSW p.Ala71Thr Uncertain significance ★ ⚠ same type
CTSW p.Arg107Lys Uncertain significance ★ ⚠ same type
CTSW p.Arg135Gln Uncertain significance ★ ⚠ same type

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/ctsw-p-pro358leu (accessed [today's date]).

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