Is TONSL p.Pro1014Leu (c.3041C>T) pathogenic?

TONSL p.Pro1014Leu (c.3041C>T) is classified Uncertain significance in TONSL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-13). AlphaMissense: likely benign (0.1716); Ultra-rare (popmax 0.0439%, sas).

How common is TONSL p.Pro1014Leu (c.3041C>T) in the general population?

TONSL p.Pro1014Leu (c.3041C>T) is ultra-rare (popmax 0.0439%, sas) (gnomAD).

What do computational predictors say about TONSL p.Pro1014Leu (c.3041C>T)?

AlphaMissense predicts likely benign (score 0.1716) — an in-silico prediction, not a clinical call.

TONSL p.Pro1014Leu

c.3041C>T · rs775868344 · VCV1431354

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1716 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0439%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1716	likely benign
REVEL	0.421	indeterminate
SaProt	LLR -9.62	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	25.0	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 0.0439% South Asian · 40/91,088 alleles

Filtering AF 0.0331% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0293%

Overall 0.0039% 63/1,613,360 alleles · ultra-rare exomes 58/1,461,032 · genomes 5/152,328 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0439%	2,277
Middle Eastern	0.0165%	6,056
Remaining individualsnot grpmax-eligible	0.0064%	15,623
East Asian	0.00446%	22,442
African / African-American	0.00133%	75,048
European (non-Finnish)	0.00127%	78,662

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.Pro1014Leu
Coding: c.3041C>T
MANE Select: NM_013432
dbSNP: rs775868344
Type: single nucleotide variant
Location: chr8:144434855 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 1014: 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

Similar variants

TONSL p.Pro1014= Likely benign ★★ same residue
TONSL p.Pro1014fs Pathogenic ★ same residue
TONSL c.1891-1G>C Pathogenic/Likely pathogenic ★★ same type
TONSL p.Arg875Ter Pathogenic/Likely pathogenic ★★ same type
TONSL p.Arg934Trp Pathogenic ★★ ⚠ same type
TONSL p.Gln177Ter Pathogenic/Likely pathogenic ★★ same type
TONSL p.Gln511Ter Pathogenic/Likely pathogenic ★★ same type
TONSL p.Glu487Lys Pathogenic/Likely pathogenic ★★ ⚠ 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/tonsl-p-pro1014leu (accessed [today's date]).

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