Is TONSL p.Pro1305Leu (c.3914C>T) pathogenic?

TONSL p.Pro1305Leu (c.3914C>T) is classified Conflicting classifications of pathogenicity in TONSL (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-12). AlphaMissense: likely benign (0.1117); Rare (popmax 0.109%, eas); Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Pro1305Leu (c.3914C>T)?

TONSL p.Pro1305Leu (c.3914C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TONSL p.Pro1305Leu (c.3914C>T) in the general population?

TONSL p.Pro1305Leu (c.3914C>T) is rare (popmax 0.109%, eas) (gnomAD).

What do computational predictors say about TONSL p.Pro1305Leu (c.3914C>T)?

AlphaMissense predicts likely benign (score 0.1117) — an in-silico prediction, not a clinical call.

TONSL p.Pro1305Leu

c.3914C>T · rs370820880 · VCV1568521

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1117 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.109%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1117	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -9.79	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.38	GERP -3.6
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	8.196	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 0.109% East Asian · 49/44,810 alleles

Filtering AF 0.0849% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0763%

Overall 0.0128% 207/1,611,932 alleles · rare exomes 182/1,459,572 · genomes 25/152,360 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.232%	430
East Asiangrpmax	0.109%	914
Admixed American	0.0134%	7,460
African / African-American	0.00133%	74,994
European (non-Finnish)	0.000339%	294,771

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro1305Leu
Coding: c.3914C>T
MANE Select: NM_013432
dbSNP: rs370820880
Type: single nucleotide variant
Location: chr8:144430433 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 1305: 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-pro1305leu (accessed [today's date]).

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