Is TONSL p.Leu1045Pro (c.3134T>C) pathogenic?

TONSL p.Leu1045Pro (c.3134T>C) is classified Likely benign in TONSL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-01). AlphaMissense: likely benign (0.0407); Very rare (popmax 0.00388%, amr); Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Leu1045Pro (c.3134T>C)?

TONSL p.Leu1045Pro (c.3134T>C) is associated with Inborn genetic diseases (ClinVar).

How common is TONSL p.Leu1045Pro (c.3134T>C) in the general population?

TONSL p.Leu1045Pro (c.3134T>C) is very rare (popmax 0.00388%, amr) (gnomAD).

What do computational predictors say about TONSL p.Leu1045Pro (c.3134T>C)?

AlphaMissense predicts likely benign (score 0.0407) — an in-silico prediction, not a clinical call.

TONSL p.Leu1045Pro

c.3134T>C · rs1029395454 · VCV2286901

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0407 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00388%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0407	likely benign
REVEL	0.163	moderately benign-leaning
SaProt	LLR -2.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.6	GERP 0.52, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	12.54	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 0.00388% Admixed American · 2/51,598 alleles

Filtering AF 0.000643% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000241%

Overall 0.000324% 5/1,544,816 alleles · very rare exomes 1/1,392,628 · genomes 4/152,188 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00388%	25,799
European (non-Finnish)	0.000262%	381,118

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: TONSL
Protein: p.Leu1045Pro
Coding: c.3134T>C
MANE Select: NM_013432
dbSNP: rs1029395454
Type: single nucleotide variant
Location: chr8:144434231 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 1045: a UniProt-annotated variant site (in semdsp; disease phenotype includes immunologic and hematologic abnormalities); a UniProt-annotated variant site (in semdsp); a UniProt-annotated variant site (in semdsp; disease phenotype includes primary aphakia and absent pupils)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TONSL p.Leu1045Ile Uncertain significance ★ ⚠ same residue
TONSL p.Ala1053Ser Uncertain significance ★★ ⚠ same condition
TONSL p.Ala1065Ser Uncertain significance ★★ ⚠ same condition
TONSL p.Ala1093Ser Uncertain significance ★★ ⚠ same condition
TONSL p.Ala1200Thr Uncertain significance ★★ ⚠ same condition
TONSL p.Ala215Thr Uncertain significance ★★ ⚠ same condition
TONSL p.Ala232Val Uncertain significance ★★ ⚠ same condition
TONSL p.Ala331Thr Uncertain significance ★★ ⚠ same condition

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/tonsl-p-leu1045pro (accessed [today's date]).

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