Is TONSL p.Arg620Gln (c.1859G>A) pathogenic?

TONSL p.Arg620Gln (c.1859G>A) is classified Uncertain significance in TONSL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-18). AlphaMissense: likely benign (0.0942); Very rare (popmax 0.004%, afr).

How common is TONSL p.Arg620Gln (c.1859G>A) in the general population?

TONSL p.Arg620Gln (c.1859G>A) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about TONSL p.Arg620Gln (c.1859G>A)?

AlphaMissense predicts likely benign (score 0.0942) — an in-silico prediction, not a clinical call.

TONSL p.Arg620Gln

c.1859G>A · rs79379836 · VCV1956715

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0942 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0942	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -9.94	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 3.3	GERP -0.84, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	21.8	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 0.004% African / African-American · 3/74,930 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00223% 36/1,611,310 alleles · very rare exomes 32/1,459,104 · genomes 4/152,206 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,977
Admixed American	0.00333%	29,995
Remaining individualsnot grpmax-eligible	0.0032%	31,222
East Asian	0.00223%	44,886
South Asian	0.0022%	45,527
European (non-Finnish)	0.00212%	47,193
Finnishnot grpmax-eligible	0.00162%	61,592

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.Arg620Gln
Coding: c.1859G>A
MANE Select: NM_013432
dbSNP: rs79379836
Type: single nucleotide variant
Location: chr8:144436788 (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

Similar variants

TONSL p.Arg620Trp Uncertain significance ★★ ⚠ same residue
TONSL p.Arg620Leu Uncertain significance ★ same residue
TONSL p.Arg620= Benign ★ 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

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-arg620gln (accessed [today's date]).

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