Is TONSL p.Val488Met (c.1462G>A) pathogenic?

TONSL p.Val488Met (c.1462G>A) is classified Benign in TONSL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1183); Common (popmax 6.64%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about TONSL p.Val488Met (c.1462G>A)?

AlphaMissense predicts likely benign (score 0.1183) — an in-silico prediction, not a clinical call.

TONSL p.Val488Met

Q: How common is TONSL p.Val488Met (c.1462G>A) in the general population?

TONSL p.Val488Met (c.1462G>A) is common (popmax 6.64%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1462G>A · rs2229314 · VCV716094

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1183 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.64%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1183	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -6.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.75	donor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -2.1	GERP -3.9
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	2.622	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 6.64% African / African-American · 4,713/70,938 alleles

Filtering AF 6.49% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.42%

Overall 0.375% 5,263/1,404,268 alleles · common exomes 2,354/1,251,906 · genomes 2,909/152,362 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.64%	15
Admixed American	0.445%	225
Remaining individualsnot grpmax-eligible	0.412%	243
Middle Eastern	0.106%	940
South Asian	0.0173%	5,784
European (non-Finnish)	0.00374%	26,770

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.Val488Met
Coding: c.1462G>A
MANE Select: NM_013432
dbSNP: rs2229314
Type: single nucleotide variant
Location: chr8:144440039 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 488: the 'disordered' region; a UniProt-annotated variant site (in semdsp; disease phenotype includes immunologic and hematologic abnormalities); a UniProt-annotated variant site (in semdsp); a UniProt-annotated variant site (in)

Full TONSL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TONSL p.Val488= Likely 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
TONSL p.Glu487Lys Pathogenic/Likely pathogenic ★★ ⚠ same type
TONSL c.2775+5G>T 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-val488met (accessed [today's date]).

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