Is SON p.Leu453Phe (c.1359G>T) pathogenic?

SON p.Leu453Phe (c.1359G>T) is classified Likely benign in SON (ClinVar, Single submitter, 2 submitters; last evaluated 2020-11-02). AlphaMissense: likely benign (0.152); Absent from gnomAD v4.1; Associated with ZTTK syndrome.

What condition is associated with SON p.Leu453Phe (c.1359G>T)?

SON p.Leu453Phe (c.1359G>T) is associated with ZTTK syndrome (ClinVar).

How common is SON p.Leu453Phe (c.1359G>T) in the general population?

SON p.Leu453Phe (c.1359G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SON p.Leu453Phe (c.1359G>T)?

AlphaMissense predicts likely benign (score 0.152) — an in-silico prediction, not a clinical call.

SON p.Leu453Phe

c.1359G>T · rs2145818992 · VCV1300898

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.152 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ZTTK syndrome

Computational evidence

Protein change
AlphaMissense	0.152	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -8.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.7, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 7,951 bp · p 0.32 · regional, not allelic
Overall
CADD	23.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SON
Protein: p.Leu453Phe
Coding: c.1359G>T
MANE Select: NM_138927
dbSNP: rs2145818992
Type: single nucleotide variant
Location: chr21:33550590 (GRCh38)
Gene constraint: LOEUF 0.051 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 36.48 · 4 PDB

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

Disease context

ZTTK syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SON c.6321+1G>A Pathogenic ★★ same condition
SON p.Arg1081Ter Pathogenic ★★ same condition
SON p.Arg1112Ter Pathogenic ★★ same condition
SON p.Arg2008Ter Pathogenic ★★ same condition
SON p.Gln96Ter Pathogenic/Likely pathogenic ★★ same condition
SON c.6657+316G>A Uncertain significance ★★ same condition
SON p.Ala817Ser Uncertain significance ★★ ⚠ same condition
SON p.Ala847Pro 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/son-p-leu453phe (accessed [today's date]).

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