Is TONSL p.Arg382His (c.1145G>A) pathogenic?

TONSL p.Arg382His (c.1145G>A) is classified Uncertain significance in TONSL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-21). AlphaMissense: likely benign (0.0999); Very rare (popmax 0.00891%, eas); Associated with TONSL-related disorder.

What condition is associated with TONSL p.Arg382His (c.1145G>A)?

TONSL p.Arg382His (c.1145G>A) is associated with TONSL-related disorder (ClinVar).

How common is TONSL p.Arg382His (c.1145G>A) in the general population?

TONSL p.Arg382His (c.1145G>A) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about TONSL p.Arg382His (c.1145G>A)?

AlphaMissense predicts likely benign (score 0.0999) — an in-silico prediction, not a clinical call.

TONSL p.Arg382His

c.1145G>A · rs370126528 · VCV1390079

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0999 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

TONSL-related disorder

Computational evidence

Protein change
AlphaMissense	0.0999	likely benign
REVEL	0.437	indeterminate
SaProt	LLR -8.19	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.86	GERP 1.6, phastCons 0.066
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	20.2	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 0.00891% East Asian · 4/44,876 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00112% 18/1,612,652 alleles · very rare exomes 13/1,460,322 · genomes 5/152,330 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,219
Admixed American	0.00666%	15,005
African / African-American	0.004%	25,018
Remaining individualsnot grpmax-eligible	0.0016%	62,472
European (non-Finnish)	0.000509%	196,639

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.Arg382His
Coding: c.1145G>A
MANE Select: NM_013432
dbSNP: rs370126528
Type: single nucleotide variant
Location: chr8:144440737 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 382: 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

TONSL-related disorder

Similar variants

TONSL p.Arg382Cys Uncertain significance ★★ ⚠ same residue
TONSL p.Arg875Ter Pathogenic/Likely pathogenic ★★ same condition
TONSL p.Gln177Ter Pathogenic/Likely pathogenic ★★ same condition
TONSL p.Glu199Lys Uncertain significance ★★ same condition
TONSL c.3007-2A>C Likely pathogenic ★ same condition
TONSL p.Gln88Ter Likely pathogenic ★ same condition
TONSL c.866-1G>C Uncertain significance ★ same condition
TONSL p.Trp110Ter 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-arg382his (accessed [today's date]).

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