Is CTSW p.Val262Met (c.784G>A) pathogenic?

CTSW p.Val262Met (c.784G>A) is classified Uncertain significance in CTSW (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-20). AlphaMissense: ambiguous (0.5428); Very rare (popmax 0.00333%, amr).

How common is CTSW p.Val262Met (c.784G>A) in the general population?

CTSW p.Val262Met (c.784G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CTSW p.Val262Met (c.784G>A)?

AlphaMissense predicts ambiguous (score 0.5428) — an in-silico prediction, not a clinical call.

CTSW p.Val262Met

c.784G>A · VCV4008198

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5428 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5428	ambiguous
REVEL	0.666	pathogenic-leaning
SaProt	LLR -12.59	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 3,760 bp · p 0.82 · regional, not allelic
Overall
CADD	26.2	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 0.00333% Admixed American · 2/59,994 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.00124% 20/1,613,970 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0064%	15,622
Admixed Americangrpmax	0.00333%	29,997
South Asian	0.0022%	45,542
European (non-Finnish)	0.00102%	98,334

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val262Met
Coding: c.784G>A
MANE Select: NM_001335
Type: single nucleotide variant
Location: chr11:65883107 (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-val262met (accessed [today's date]).

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