Is TONSL p.Arg543His (c.1628G>A) pathogenic?

TONSL p.Arg543His (c.1628G>A) is classified Uncertain significance in TONSL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-03). AlphaMissense: likely benign (0.0835); Ultra-rare (popmax 0.0173%, afr); Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Arg543His (c.1628G>A)?

TONSL p.Arg543His (c.1628G>A) is associated with Inborn genetic diseases (ClinVar).

How common is TONSL p.Arg543His (c.1628G>A) in the general population?

TONSL p.Arg543His (c.1628G>A) is ultra-rare (popmax 0.0173%, afr) (gnomAD).

What do computational predictors say about TONSL p.Arg543His (c.1628G>A)?

AlphaMissense predicts likely benign (score 0.0835) — an in-silico prediction, not a clinical call.

TONSL p.Arg543His

c.1628G>A · rs753535876 · VCV1425591

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0835 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0173%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0835	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -8.03	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 0.003	GERP -0.75, phastCons 0.2
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	18.2	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 0.0173% African / African-American · 13/74,930 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00813%

Overall 0.00645% 104/1,612,940 alleles · ultra-rare exomes 93/1,460,704 · genomes 11/152,236 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0173%	5,764
European (non-Finnish)	0.00703%	14,216
Remaining individualsnot grpmax-eligible	0.0048%	20,821
Finnishnot grpmax-eligible	0.00476%	21,011
East Asian	0.00223%	44,896
Admixed American	0.00167%	59,990

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.Arg543His
Coding: c.1628G>A
MANE Select: NM_013432
dbSNP: rs753535876
Type: single nucleotide variant
Location: chr8:144438496 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 543: 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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TONSL p.Arg543Cys Uncertain significance ★★ ⚠ 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
TONSL p.Ala232Val Uncertain significance ★★ ⚠ same condition
TONSL p.Ala331Thr 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-arg543his (accessed [today's date]).

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