Is SON p.Glu1546= (c.4638A>G) pathogenic?

SON p.Glu1546= (c.4638A>G) is classified Conflicting classifications of pathogenicity in SON (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-11-01). Very rare (popmax 0.00167%, amr); Associated with ZTTK syndrome.

What condition is associated with SON p.Glu1546= (c.4638A>G)?

SON p.Glu1546= (c.4638A>G) is associated with ZTTK syndrome (ClinVar).

How common is SON p.Glu1546= (c.4638A>G) in the general population?

SON p.Glu1546= (c.4638A>G) is very rare (popmax 0.00167%, amr) (gnomAD).

SON p.Glu1546=

c.4638A>G · rs758818850 · VCV737289

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

ZTTK syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.056	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.82, phastCons 0.96
Overall
CADD	4.114	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,006 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000248% 4/1,613,952 alleles · very rare exomes 2/1,461,722 · genomes 2/152,230 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,006
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)	0.000169%	589,984

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: SON
Protein: p.Glu1546=
Coding: c.4638A>G
MANE Select: NM_138927
dbSNP: rs758818850
Type: single nucleotide variant
Location: chr21:33553869 (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-glu1546 (accessed [today's date]).

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