Is TONSL p.Pro1276Leu (c.3827C>T) pathogenic?

TONSL p.Pro1276Leu (c.3827C>T) is classified Benign in TONSL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1281); Common (popmax 5.58%, amr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about TONSL p.Pro1276Leu (c.3827C>T)?

AlphaMissense predicts likely benign (score 0.1281) — an in-silico prediction, not a clinical call.

TONSL p.Pro1276Leu

Q: How common is TONSL p.Pro1276Leu (c.3827C>T) in the general population?

TONSL p.Pro1276Leu (c.3827C>T) is common (popmax 5.58%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3827C>T · rs4925856 · VCV1164724

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1281 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.58%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1281	likely benign
REVEL	0.133	moderately benign-leaning
SaProt	LLR -7.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.37 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.9	GERP -1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	21.1	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 5.58% Admixed American · 3,328/59,634 alleles

Filtering AF 5.42% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.36%

Overall 0.218% 3,521/1,612,244 alleles · common exomes 2,956/1,459,884 · genomes 565/152,360 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	5.58%	18
Remaining individualsnot grpmax-eligible	0.216%	462
African / African-American	0.044%	2,273
South Asian	0.0022%	45,413
European (non-Finnish)	0.00195%	51,271

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.Pro1276Leu
Coding: c.3827C>T
MANE Select: NM_013432
dbSNP: rs4925856
Type: single nucleotide variant
Location: chr8:144430520 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 1276: 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); a UniProt-annotated variant site (in)

Full TONSL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TONSL p.Pro1276= Likely benign ★ same residue
TONSL c.1891-1G>C Pathogenic/Likely pathogenic ★★ same type
TONSL p.Arg875Ter Pathogenic/Likely pathogenic ★★ same type
TONSL p.Arg934Trp Pathogenic ★★ ⚠ same type
TONSL p.Gln177Ter Pathogenic/Likely pathogenic ★★ same type
TONSL p.Gln511Ter Pathogenic/Likely pathogenic ★★ same type
TONSL p.Glu487Lys Pathogenic/Likely pathogenic ★★ ⚠ same type
TONSL c.2775+5G>T Uncertain significance ★★ same type

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-pro1276leu (accessed [today's date]).

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