Is TONSL p.Leu1272Phe (c.3814C>T) pathogenic?

TONSL p.Leu1272Phe (c.3814C>T) is classified Uncertain significance in TONSL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-04). AlphaMissense: likely benign (0.1384); Very rare (popmax 0.00338%, amr); Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Leu1272Phe (c.3814C>T)?

TONSL p.Leu1272Phe (c.3814C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TONSL p.Leu1272Phe (c.3814C>T) in the general population?

TONSL p.Leu1272Phe (c.3814C>T) is very rare (popmax 0.00338%, amr) (gnomAD).

What do computational predictors say about TONSL p.Leu1272Phe (c.3814C>T)?

AlphaMissense predicts likely benign (score 0.1384) — an in-silico prediction, not a clinical call.

TONSL p.Leu1272Phe

c.3814C>T · rs782477480 · VCV2616329

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1384 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00338%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1384	likely benign
REVEL	0.425	indeterminate
SaProt	LLR -8.52	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00338% Admixed American · 2/59,094 alleles

Filtering AF 0.000561% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00021%

Overall 0.000124% 2/1,609,444 alleles · very rare exomes 2/1,457,084 · genomes 0/152,360 · 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.Leu1272Phe
Coding: c.3814C>T
MANE Select: NM_013432
dbSNP: rs782477480
Type: single nucleotide variant
Location: chr8:144430533 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 1272: 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-leu1272phe (accessed [today's date]).

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