Is TONSL p.Arg579Cys (c.1735C>T) pathogenic?

TONSL p.Arg579Cys (c.1735C>T) is classified Uncertain significance in TONSL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-31). AlphaMissense: likely benign (0.1073); Rare (popmax 0.165%, mid).

How common is TONSL p.Arg579Cys (c.1735C>T) in the general population?

TONSL p.Arg579Cys (c.1735C>T) is rare (popmax 0.165%, mid) (gnomAD).

What do computational predictors say about TONSL p.Arg579Cys (c.1735C>T)?

AlphaMissense predicts likely benign (score 0.1073) — an in-silico prediction, not a clinical call.

TONSL p.Arg579Cys

c.1735C>T · rs201525526 · VCV1037653

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1073 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.165%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1073	likely benign
REVEL	0.383	indeterminate
SaProt	LLR -11.37	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.8	GERP 1.5, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	32.0	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 0.165% Middle Eastern · 10/6,058 alleles

Filtering AF 0.0895% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0681%

Overall 0.0127% 204/1,608,756 alleles · rare exomes 183/1,456,420 · genomes 21/152,336 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.165%	606
Admixed American	0.0383%	2,608
Ashkenazi Jewishnot grpmax-eligible	0.0372%	2,688
Remaining individualsnot grpmax-eligible	0.0144%	6,934
European (non-Finnish)	0.0112%	8,931
South Asian	0.00989%	10,116
African / African-American	0.008%	12,507
East Asian	0.00446%	22,422
Finnishnot grpmax-eligible	0.00334%	29,975

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.Arg579Cys
Coding: c.1735C>T
MANE Select: NM_013432
dbSNP: rs201525526
Type: single nucleotide variant
Location: chr8:144436912 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 579: a UniProt-annotated variant site (in semdsp; disease phenotype includes immunologic and hematologic abnormalities); a UniProt-annotated variant site (in semdsp); an α-helix

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

Similar variants

TONSL p.Arg579His Conflicting classifications of pathogenicity ★ ⚠ 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
TONSL c.2775+5G>T 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/tonsl-p-arg579cys (accessed [today's date]).

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