Is TONSL p.Arg849His (c.2546G>A) pathogenic?

TONSL p.Arg849His (c.2546G>A) is classified Conflicting classifications of pathogenicity in TONSL (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-10-17). AlphaMissense: likely benign (0.0714); Ultra-rare (popmax 0.0166%, mid).

How common is TONSL p.Arg849His (c.2546G>A) in the general population?

TONSL p.Arg849His (c.2546G>A) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about TONSL p.Arg849His (c.2546G>A)?

AlphaMissense predicts likely benign (score 0.0714) — an in-silico prediction, not a clinical call.

TONSL p.Arg849His

c.2546G>A · rs767466576 · VCV1435617

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0714 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0714	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -8.68	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 -2.6	GERP -2.5
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	10.66	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 0.0166% Middle Eastern · 1/6,026 alleles

Filtering AF 0.014% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0133%

Overall 0.0129% 206/1,597,786 alleles · ultra-rare exomes 186/1,445,672 · genomes 20/152,114 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,026
European (non-Finnish)	0.0159%	6,284
Remaining individualsnot grpmax-eligible	0.0114%	8,808
African / African-American	0.0107%	9,323
Ashkenazi Jewishnot grpmax-eligible	0.00343%	29,192
Admixed American	0.00168%	59,464
Finnishnot grpmax-eligible	0.00161%	62,174
South Asian	0.00111%	90,446

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.Arg849His
Coding: c.2546G>A
MANE Select: NM_013432
dbSNP: rs767466576
Type: single nucleotide variant
Location: chr8:144435887 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 849: 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 semdsp; disease phenotype includes primary aphakia and absent pupils)

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

Similar variants

TONSL p.Arg849Cys Uncertain significance ★ ⚠ 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-arg849his (accessed [today's date]).

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