Is TONSL p.Val996Met (c.2986G>A) pathogenic?

TONSL p.Val996Met (c.2986G>A) is classified Uncertain significance in TONSL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-06). AlphaMissense: ambiguous (0.5246); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Val996Met (c.2986G>A)?

TONSL p.Val996Met (c.2986G>A) is associated with Inborn genetic diseases (ClinVar).

How common is TONSL p.Val996Met (c.2986G>A) in the general population?

TONSL p.Val996Met (c.2986G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TONSL p.Val996Met (c.2986G>A)?

AlphaMissense predicts ambiguous (score 0.5246) — an in-silico prediction, not a clinical call.

TONSL p.Val996Met

c.2986G>A · rs1823379103 · VCV2494223

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5246 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5246	ambiguous
REVEL	0.174	moderately benign-leaning
SaProt	LLR -9.97	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	24.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TONSL
Protein: p.Val996Met
Coding: c.2986G>A
MANE Select: NM_013432
dbSNP: rs1823379103
Type: single nucleotide variant
Location: chr8:144435037 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 996: 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

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-val996met (accessed [today's date]).

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