Is TONSL p.Arg977Ser (c.2931G>C) pathogenic?

TONSL p.Arg977Ser (c.2931G>C) is classified Uncertain significance in TONSL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-12-02). AlphaMissense: ambiguous (0.3571); Very rare (popmax 0.00169%, amr); Associated with Inborn genetic diseases.

What condition is associated with TONSL p.Arg977Ser (c.2931G>C)?

TONSL p.Arg977Ser (c.2931G>C) is associated with Inborn genetic diseases (ClinVar).

How common is TONSL p.Arg977Ser (c.2931G>C) in the general population?

TONSL p.Arg977Ser (c.2931G>C) is very rare (popmax 0.00169%, amr) (gnomAD).

What do computational predictors say about TONSL p.Arg977Ser (c.2931G>C)?

AlphaMissense predicts ambiguous (score 0.3571) — an in-silico prediction, not a clinical call.

TONSL p.Arg977Ser

c.2931G>C · rs1586686043 · VCV1981303

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3571 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00169%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3571	ambiguous
REVEL	0.125	moderately benign-leaning
SaProt	LLR -4.97	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.36	GERP -0.86, phastCons 0.14
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	22.0	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 0.00169% Admixed American · 1/59,034 alleles

Overall 0.000187% 3/1,605,256 alleles · very rare exomes 3/1,452,900 · genomes 0/152,356 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00169%	59,034
South Asian	0.00111%	89,916
European (non-Finnish)	8.5e-05%	1,176,548

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.Arg977Ser
Coding: c.2931G>C
MANE Select: NM_013432
dbSNP: rs1586686043
Type: single nucleotide variant
Location: chr8:144435092 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 977: 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-arg977ser (accessed [today's date]).

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