Is TONSL p.Phe1174Leu (c.3520T>C) pathogenic?

TONSL p.Phe1174Leu (c.3520T>C) is classified Benign in TONSL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-28). AlphaMissense: ambiguous (0.4226); Low-frequency (popmax 4.72%, afr).

How common is TONSL p.Phe1174Leu (c.3520T>C) in the general population?

TONSL p.Phe1174Leu (c.3520T>C) is low-frequency (popmax 4.72%, afr) (gnomAD).

What do computational predictors say about TONSL p.Phe1174Leu (c.3520T>C)?

AlphaMissense predicts ambiguous (score 0.4226) — an in-silico prediction, not a clinical call.

TONSL p.Phe1174Leu

c.3520T>C · rs35351970 · VCV1168131

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4226 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.72%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4226	ambiguous
REVEL	0.061	moderately benign-leaning
SaProt	LLR -5.60	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 3.4	GERP -1.5, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 15 kb · p 0.67 · regional, not allelic
Overall
CADD	10.16	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 4.72% African / African-American · 3,540/75,042 alleles

Filtering AF 4.59% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.53%

Overall 0.247% 3,986/1,613,460 alleles · low-frequency exomes 1,937/1,461,132 · genomes 2,049/152,328 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.72%	21
Admixed American	0.293%	341
Remaining individualsnot grpmax-eligible	0.262%	381
Middle Eastern	0.0495%	2,019
South Asian	0.00878%	11,386
European (non-Finnish)	0.00805%	12,421

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.Phe1174Leu
Coding: c.3520T>C
MANE Select: NM_013432
dbSNP: rs35351970
Type: single nucleotide variant
Location: chr8:144433627 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.06 · 3 PDB
Residue 1174: 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 p.Phe1174= 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-phe1174leu (accessed [today's date]).

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