Is TONSL p.Glu79Lys (c.235G>A) pathogenic?

TONSL p.Glu79Lys (c.235G>A) is classified Uncertain significance in TONSL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-02-23). AlphaMissense: ambiguous (0.5191); Very rare (popmax 0.0014%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Glu79Lys (c.235G>A)?

TONSL p.Glu79Lys (c.235G>A) is associated with Inborn genetic diseases (ClinVar).

How common is TONSL p.Glu79Lys (c.235G>A) in the general population?

TONSL p.Glu79Lys (c.235G>A) is very rare (popmax 0.0014%, nfe) (gnomAD).

What do computational predictors say about TONSL p.Glu79Lys (c.235G>A)?

AlphaMissense predicts ambiguous (score 0.5191) — an in-silico prediction, not a clinical call.

TONSL p.Glu79Lys

c.235G>A · rs1172331406 · VCV1945445

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5191 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0014%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5191	ambiguous
REVEL	0.387	indeterminate
SaProt	LLR -7.29	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	28.5	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 0.0014% European (non-Finnish) · 16/1,146,688 alleles

Filtering AF 0.000826% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00104% 16/1,545,376 alleles · very rare exomes 14/1,393,118 · genomes 2/152,258 · joint denominator

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.Glu79Lys
Coding: c.235G>A
MANE Select: NM_013432
dbSNP: rs1172331406
Type: single nucleotide variant
Location: chr8:144443911 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB

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-glu79lys (accessed [today's date]).

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