Is TONSL p.Ala921Pro (c.2761G>C) pathogenic?

TONSL p.Ala921Pro (c.2761G>C) is classified Uncertain significance in TONSL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-20). AlphaMissense: likely benign (0.0739); Ultra-rare (popmax 0.051%, mid).

How common is TONSL p.Ala921Pro (c.2761G>C) in the general population?

TONSL p.Ala921Pro (c.2761G>C) is ultra-rare (popmax 0.051%, mid) (gnomAD).

What do computational predictors say about TONSL p.Ala921Pro (c.2761G>C)?

AlphaMissense predicts likely benign (score 0.0739) — an in-silico prediction, not a clinical call.

TONSL p.Ala921Pro

c.2761G>C · rs200025720 · VCV1420304

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0739 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.051%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0739	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -5.58	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 -0.39	GERP -2.7
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	8.259	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 0.051% Middle Eastern · 3/5,882 alleles

Filtering AF 0.0178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0169%

Overall 0.016% 256/1,603,770 alleles · ultra-rare exomes 226/1,451,476 · genomes 30/152,294 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.051%	1,961
European (non-Finnish)	0.0199%	5,034
Remaining individualsnot grpmax-eligible	0.00807%	12,399
Admixed American	0.00669%	14,943
South Asian	0.00661%	15,117
African / African-American	0.00401%	24,953
Ashkenazi Jewishnot grpmax-eligible	0.00341%	29,350
Finnishnot grpmax-eligible	0.0016%	62,670

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.Ala921Pro
Coding: c.2761G>C
MANE Select: NM_013432
dbSNP: rs200025720
Type: single nucleotide variant
Location: chr8:144435672 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 921: the 'disordered' region; 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

Similar variants

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
TONSL p.Ala1053Ser 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-ala921pro (accessed [today's date]).

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