Is TONSL p.Arg339His (c.1016G>A) pathogenic?

TONSL p.Arg339His (c.1016G>A) is classified Conflicting classifications of pathogenicity in TONSL (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-01-01). AlphaMissense: likely benign (0.0575); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Arg339His (c.1016G>A)?

TONSL p.Arg339His (c.1016G>A) is associated with Inborn genetic diseases (ClinVar).

How common is TONSL p.Arg339His (c.1016G>A) in the general population?

TONSL p.Arg339His (c.1016G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about TONSL p.Arg339His (c.1016G>A)?

AlphaMissense predicts likely benign (score 0.0575) — an in-silico prediction, not a clinical call.

TONSL p.Arg339His

c.1016G>A · rs199658960 · VCV1429988

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0575 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0575	likely benign
REVEL	0.145	moderately benign-leaning
SaProt	LLR -5.57	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 -4.6	GERP -1.3
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	4.039	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00211% 34/1,612,650 alleles · ultra-rare exomes 32/1,460,444 · genomes 2/152,206 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Admixed American	0.005%	19,998
Remaining individualsnot grpmax-eligible	0.0032%	31,228
South Asian	0.0022%	45,542
European (non-Finnish)	0.00212%	47,196
African / African-American	0.00133%	74,928

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.Arg339His
Coding: c.1016G>A
MANE Select: NM_013432
dbSNP: rs199658960
Type: single nucleotide variant
Location: chr8:144440866 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 339: 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.Arg339Cys Uncertain significance ★ ⚠ same residue
TONSL p.Arg339= Likely benign ★ 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

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-arg339his (accessed [today's date]).

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