Is TONSL p.Arg214Cys (c.640C>T) pathogenic?

TONSL p.Arg214Cys (c.640C>T) is classified Uncertain significance in TONSL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-05). AlphaMissense: likely benign (0.1427); Very rare (popmax 0.0017%, amr); Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Arg214Cys (c.640C>T)?

TONSL p.Arg214Cys (c.640C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TONSL p.Arg214Cys (c.640C>T) in the general population?

TONSL p.Arg214Cys (c.640C>T) is very rare (popmax 0.0017%, amr) (gnomAD).

What do computational predictors say about TONSL p.Arg214Cys (c.640C>T)?

AlphaMissense predicts likely benign (score 0.1427) — an in-silico prediction, not a clinical call.

TONSL p.Arg214Cys

c.640C>T · rs763013214 · VCV1436192

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1427 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0017%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1427	likely benign
REVEL	0.605	indeterminate
SaProt	LLR -10.89	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP 0.41, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	29.3	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 0.0017% Admixed American · 1/58,814 alleles

Filtering AF 0.000364% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000263%

Overall 0.000692% 11/1,590,298 alleles · very rare exomes 11/1,437,928 · genomes 0/152,370 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0017%	58,814
Finnishnot grpmax-eligible	0.00165%	60,428
European (non-Finnish)	0.000773%	129,389

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.Arg214Cys
Coding: c.640C>T
MANE Select: NM_013432
dbSNP: rs763013214
Type: single nucleotide variant
Location: chr8:144442351 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 214: 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.Arg214Leu Uncertain significance ★★ ⚠ same residue
TONSL p.Arg214His Uncertain significance ★ ⚠ same residue
TONSL p.Arg214= 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

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-arg214cys (accessed [today's date]).

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