Is CTSL p.Met75Ile (c.225G>A) pathogenic?

CTSL p.Met75Ile (c.225G>A) is classified Uncertain significance in CTSL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-26). AlphaMissense: likely pathogenic (0.7037); Absent from gnomAD v4.1.

How common is CTSL p.Met75Ile (c.225G>A) in the general population?

CTSL p.Met75Ile (c.225G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CTSL p.Met75Ile (c.225G>A)?

AlphaMissense predicts likely pathogenic (score 0.7037) — an in-silico prediction, not a clinical call.

CTSL p.Met75Ile

c.225G>A · VCV3498469

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7037 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7037	likely pathogenic
REVEL	0.457	indeterminate
SaProt	LLR -9.68	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP -0.22, phastCons 0.99
Regional constraint	o/e 0.89	unconstrained · MANE · 3,500 bp · p 0.025 · regional, not allelic
Overall
CADD	22.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CTSL
Protein: p.Met75Ile
Coding: c.225G>A
MANE Select: NM_001912
Type: single nucleotide variant
Location: chr9:87728125 (GRCh38)
Gene constraint: LOEUF 0.932 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.75 · 64 PDB
Residue 75: a β-strand

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

Similar variants

CTSL p.Met75Thr Uncertain significance ★ ⚠ same residue
CTSL p.Thr207Ile Uncertain significance ★★ ⚠ same type
CTSL p.Ser117Tyr Benign ★★ ⚠ same type
CTSL p.Ala143Thr Uncertain significance ★ ⚠ same type
CTSL p.Ala15Val Uncertain significance ★ ⚠ same type
CTSL p.Ala220Gly Uncertain significance ★ ⚠ same type
CTSL p.Ala50Gly Uncertain significance ★ ⚠ same type
CTSL p.Arg153Gln 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/ctsl-p-met75ile (accessed [today's date]).

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