Is TONSL p.Asp650Glu (c.1950C>G) pathogenic?

TONSL p.Asp650Glu (c.1950C>G) is classified Likely benign in TONSL (ClinVar, Single submitter, 2 submitters; last evaluated 2026-01-26). AlphaMissense: likely pathogenic (0.7647); Rare (popmax 0.212%, nfe).

How common is TONSL p.Asp650Glu (c.1950C>G) in the general population?

TONSL p.Asp650Glu (c.1950C>G) is rare (popmax 0.212%, nfe) (gnomAD).

What do computational predictors say about TONSL p.Asp650Glu (c.1950C>G)?

AlphaMissense predicts likely pathogenic (score 0.7647) — an in-silico prediction, not a clinical call.

TONSL p.Asp650Glu

c.1950C>G · rs141505364 · VCV1632359

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7647 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.212%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7647	likely pathogenic
REVEL	0.237	benign-leaning
SaProt	LLR -9.17	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5	GERP 1.5, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	22.4	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 0.212% European (non-Finnish) · 2,507/1,179,940 alleles

Filtering AF 0.206% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.203%

Overall 0.173% 2,791/1,612,080 alleles · rare exomes 2,617/1,459,756 · genomes 174/152,324 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.319%	313
European (non-Finnish)grpmax	0.212%	471
Remaining individualsnot grpmax-eligible	0.0848%	1,179
African / African-American	0.0333%	3,002
Admixed American	0.0117%	8,575
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,590

Finnish 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.Asp650Glu
Coding: c.1950C>G
MANE Select: NM_013432
dbSNP: rs141505364
Type: single nucleotide variant
Location: chr8:144436622 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 650: a UniProt-annotated variant site (in semdsp; disease phenotype includes immunologic and hematologic abnormalities); a UniProt-annotated variant site (in semdsp)

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-asp650glu (accessed [today's date]).

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