Is TONSL p.Arg875Pro (c.2624G>C) pathogenic?

TONSL p.Arg875Pro (c.2624G>C) is classified Likely benign in TONSL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.1116); Rare (popmax 0.518%, afr).

How common is TONSL p.Arg875Pro (c.2624G>C) in the general population?

TONSL p.Arg875Pro (c.2624G>C) is rare (popmax 0.518%, afr) (gnomAD).

What do computational predictors say about TONSL p.Arg875Pro (c.2624G>C)?

AlphaMissense predicts likely benign (score 0.1116) — an in-silico prediction, not a clinical call.

TONSL p.Arg875Pro

c.2624G>C · rs147256304 · VCV1652159

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1116 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.518%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1116	likely benign
REVEL	0.271	benign-leaning
SaProt	LLR -6.45	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 -3.6	GERP -3
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	3.7	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 0.518% African / African-American · 388/74,956 alleles

Filtering AF 0.475% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.458%

Overall 0.0285% 459/1,612,650 alleles · rare exomes 230/1,460,562 · genomes 229/152,088 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.518%	193
Middle Eastern	0.066%	1,515
Remaining individualsnot grpmax-eligible	0.0384%	2,604
Admixed American	0.03%	3,334
European (non-Finnish)	0.00212%	47,193

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.Arg875Pro
Coding: c.2624G>C
MANE Select: NM_013432
dbSNP: rs147256304
Type: single nucleotide variant
Location: chr8:144435809 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 875: 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.Arg875Ter Pathogenic/Likely pathogenic ★★ same residue
TONSL p.Arg875Gln Uncertain significance ★★ ⚠ same residue
TONSL c.1891-1G>C 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-arg875pro (accessed [today's date]).

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