Is TONSL p.Lys237Arg (c.710A>G) pathogenic?

TONSL p.Lys237Arg (c.710A>G) is classified Conflicting classifications of pathogenicity in TONSL (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-03). AlphaMissense: likely benign (0.0776); Rare (popmax 0.272%, afr); Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Lys237Arg (c.710A>G)?

TONSL p.Lys237Arg (c.710A>G) is associated with Inborn genetic diseases (ClinVar).

How common is TONSL p.Lys237Arg (c.710A>G) in the general population?

TONSL p.Lys237Arg (c.710A>G) is rare (popmax 0.272%, afr) (gnomAD).

What do computational predictors say about TONSL p.Lys237Arg (c.710A>G)?

AlphaMissense predicts likely benign (score 0.0776) — an in-silico prediction, not a clinical call.

TONSL p.Lys237Arg

c.710A>G · rs145201012 · VCV1649887

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0776 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.272%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0776	likely benign
REVEL	0.075	moderately benign-leaning
SaProt	LLR -5.83	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 -0.46	GERP -2.1, phastCons 0.001
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	5.333	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 0.272% African / African-American · 203/74,704 alleles

Filtering AF 0.241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.229%

Overall 0.0141% 225/1,596,246 alleles · rare exomes 110/1,443,924 · genomes 115/152,322 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.272%	368
Remaining individualsnot grpmax-eligible	0.0211%	4,742
Middle Eastern	0.0167%	6,006
Admixed American	0.00675%	14,822
European (non-Finnish)	0.000343%	291,898

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.Lys237Arg
Coding: c.710A>G
MANE Select: NM_013432
dbSNP: rs145201012
Type: single nucleotide variant
Location: chr8:144442281 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 237: 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

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

Similar variants

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
TONSL p.Ala478Glu 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-lys237arg (accessed [today's date]).

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