Is CTSW p.Ile264Ser (c.791T>G) pathogenic?

CTSW p.Ile264Ser (c.791T>G) is classified Uncertain significance in CTSW (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-15). AlphaMissense: likely pathogenic (0.9168); Very rare (popmax 0.00223%, eas).

How common is CTSW p.Ile264Ser (c.791T>G) in the general population?

CTSW p.Ile264Ser (c.791T>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CTSW p.Ile264Ser (c.791T>G)?

AlphaMissense predicts likely pathogenic (score 0.9168) — an in-silico prediction, not a clinical call.

CTSW p.Ile264Ser

c.791T>G · VCV3498484

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9168 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9168	likely pathogenic · top 8% in CTSW
REVEL	0.467	indeterminate
SaProt	LLR -13.61	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 3,760 bp · p 0.82 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00223% East Asian · 1/44,890 alleles

Overall 0.000186% 3/1,613,844 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,890
African / African-American	0.00134%	74,812
European (non-Finnish)	8.47e-05%	1,179,997

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.Ile264Ser
Coding: c.791T>G
MANE Select: NM_001335
Type: single nucleotide variant
Location: chr11:65883114 (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.Ile264Val Uncertain significance ★ ⚠ same residue
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

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-ile264ser (accessed [today's date]).

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