Is TONSL p.Arg620Trp (c.1858C>T) pathogenic?

TONSL p.Arg620Trp (c.1858C>T) is classified Uncertain significance in TONSL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-07). AlphaMissense: likely benign (0.2464); Ultra-rare (popmax 0.0329%, mid); Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Arg620Trp (c.1858C>T)?

TONSL p.Arg620Trp (c.1858C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TONSL p.Arg620Trp (c.1858C>T) in the general population?

TONSL p.Arg620Trp (c.1858C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about TONSL p.Arg620Trp (c.1858C>T)?

AlphaMissense predicts likely benign (score 0.2464) — an in-silico prediction, not a clinical call.

TONSL p.Arg620Trp

c.1858C>T · VCV3609586

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2464 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2464	likely benign
REVEL	0.465	indeterminate
SaProt	LLR -13.02	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP 1.5, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	26.2	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 0.0329% Middle Eastern · 2/6,080 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00217% 35/1,611,260 alleles · ultra-rare exomes 34/1,459,084 · genomes 1/152,176 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,040
East Asian	0.00668%	14,963
Remaining individualsnot grpmax-eligible	0.0032%	31,226
European (non-Finnish)	0.00237%	42,138

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.Arg620Trp
Coding: c.1858C>T
MANE Select: NM_013432
Type: single nucleotide variant
Location: chr8:144436789 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 620: a UniProt-annotated variant site (in semdsp; disease phenotype includes immunologic and hematologic abnormalities); a UniProt-annotated variant site (in semdsp)

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.Arg620Leu Uncertain significance ★ same residue
TONSL p.Arg620Gln Uncertain significance ★ ⚠ same residue
TONSL p.Arg620= Benign ★ 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

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-arg620trp (accessed [today's date]).

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