Is TONSL p.Val545Ile (c.1633G>A) pathogenic?

TONSL p.Val545Ile (c.1633G>A) is classified Likely benign in TONSL (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-18). AlphaMissense: likely benign (0.1958); Rare (popmax 0.332%, eas).

How common is TONSL p.Val545Ile (c.1633G>A) in the general population?

TONSL p.Val545Ile (c.1633G>A) is rare (popmax 0.332%, eas) (gnomAD).

What do computational predictors say about TONSL p.Val545Ile (c.1633G>A)?

AlphaMissense predicts likely benign (score 0.1958) — an in-silico prediction, not a clinical call.

TONSL p.Val545Ile

c.1633G>A · rs202000622 · VCV1658833

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1958 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.332%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1958	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -12.82	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.8	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	23.4	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 0.332% East Asian · 149/44,884 alleles

Filtering AF 0.288% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.272%

Overall 0.0172% 278/1,613,002 alleles · rare exomes 230/1,460,650 · genomes 48/152,352 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.332%	301
Ashkenazi Jewishnot grpmax-eligible	0.199%	501
Remaining individualsnot grpmax-eligible	0.032%	3,124
Admixed American	0.0217%	4,616
Middle Eastern	0.0165%	6,056
South Asian	0.00659%	15,180
African / African-American	0.00533%	18,764
Finnishnot grpmax-eligible	0.00318%	31,491
European (non-Finnish)	0.00203%	49,165

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.Val545Ile
Coding: c.1633G>A
MANE Select: NM_013432
dbSNP: rs202000622
Type: single nucleotide variant
Location: chr8:144438491 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 545: 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

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-val545ile (accessed [today's date]).

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