Is TONSL p.Phe944Val (c.2830T>G) pathogenic?

TONSL p.Phe944Val (c.2830T>G) is classified Uncertain significance in TONSL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-07). AlphaMissense: likely pathogenic (0.874); Ultra-rare (popmax 0.0506%, mid); Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Phe944Val (c.2830T>G)?

TONSL p.Phe944Val (c.2830T>G) is associated with Inborn genetic diseases (ClinVar).

How common is TONSL p.Phe944Val (c.2830T>G) in the general population?

TONSL p.Phe944Val (c.2830T>G) is ultra-rare (popmax 0.0506%, mid) (gnomAD).

What do computational predictors say about TONSL p.Phe944Val (c.2830T>G)?

AlphaMissense predicts likely pathogenic (score 0.874) — an in-silico prediction, not a clinical call.

TONSL p.Phe944Val

c.2830T>G · rs2537485619 · VCV2282249

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.874 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0506%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.874	likely pathogenic · top 8% in TONSL
REVEL	0.36	indeterminate
SaProt	LLR -11.18	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0506% Middle Eastern · 3/5,934 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00733%

Overall 0.00336% 52/1,545,432 alleles · ultra-rare exomes 52/1,393,322 · genomes 0/152,110 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0506%	1,978
East Asian	0.0123%	8,120
Finnishnot grpmax-eligible	0.00852%	11,740
Remaining individualsnot grpmax-eligible	0.00502%	19,938
Ashkenazi Jewishnot grpmax-eligible	0.00352%	28,392
European (non-Finnish)	0.00297%	33,635
African / African-American	0.00137%	73,022

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.Phe944Val
Coding: c.2830T>G
MANE Select: NM_013432
dbSNP: rs2537485619
Type: single nucleotide variant
Location: chr8:144435496 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 944: 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-phe944val (accessed [today's date]).

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