Is CTSL p.Asn43Asp (c.127A>G) pathogenic?

CTSL p.Asn43Asp (c.127A>G) is classified Uncertain significance in CTSL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-16). AlphaMissense: likely benign (0.0868); Very rare (popmax 0.005%, amr).

How common is CTSL p.Asn43Asp (c.127A>G) in the general population?

CTSL p.Asn43Asp (c.127A>G) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about CTSL p.Asn43Asp (c.127A>G)?

AlphaMissense predicts likely benign (score 0.0868) — an in-silico prediction, not a clinical call.

CTSL p.Asn43Asp

c.127A>G · VCV3498468

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0868 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0868	likely benign
REVEL	0.143	moderately benign-leaning
SaProt	LLR -6.16	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.7	GERP -2.9
Regional constraint	o/e 0.89	unconstrained · MANE · 3,500 bp · p 0.025 · regional, not allelic
Overall
CADD	11.56	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.005% Admixed American · 3/60,016 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000205% 3/1,461,328 alleles · very rare

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: CTSL
Protein: p.Asn43Asp
Coding: c.127A>G
MANE Select: NM_001912
Type: single nucleotide variant
Location: chr9:87728027 (GRCh38)
Gene constraint: LOEUF 0.932 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.75 · 64 PDB
Residue 43: a turn

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

Similar variants

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
CTSL p.Arg153Trp 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-asn43asp (accessed [today's date]).

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