Is TONSL p.Asn526= (c.1578C>T) pathogenic?

TONSL p.Asn526= (c.1578C>T) is classified Benign in TONSL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-01). Rare (popmax 0.264%, mid).

How common is TONSL p.Asn526= (c.1578C>T) in the general population?

TONSL p.Asn526= (c.1578C>T) is rare (popmax 0.264%, mid) (gnomAD).

TONSL p.Asn526=

c.1578C>T · rs150430814 · VCV1165266

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.264%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -4.2	GERP -2.5
Overall
CADD	1.14	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.264% Middle Eastern · 16/6,060 alleles

Filtering AF 0.166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.144%

Overall 0.0989% 1,596/1,612,942 alleles · rare exomes 1,373/1,460,748 · genomes 223/152,194 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	3.53%	28
Middle Easterngrpmax	0.264%	379
Remaining individualsnot grpmax-eligible	0.23%	434
Admixed American	0.182%	551
African / African-American	0.0773%	1,294
European (non-Finnish)	0.0185%	5,412
South Asian	0.00439%	22,767
Finnishnot grpmax-eligible	0.00317%	31,545
East Asian	0.00223%	44,868

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asn526=
Coding: c.1578C>T
MANE Select: NM_013432
dbSNP: rs150430814
Type: single nucleotide variant
Location: chr8:144438546 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 526: 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 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
TONSL p.Ala1053Ser 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-asn526 (accessed [today's date]).

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