Is SON p.Pro507Arg (c.1520C>G) pathogenic?

SON p.Pro507Arg (c.1520C>G) is classified Uncertain significance in SON (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-22). AlphaMissense: ambiguous (0.4848); Very rare (popmax 0.00223%, eas); Associated with ZTTK syndrome.

What condition is associated with SON p.Pro507Arg (c.1520C>G)?

SON p.Pro507Arg (c.1520C>G) is associated with ZTTK syndrome (ClinVar).

How common is SON p.Pro507Arg (c.1520C>G) in the general population?

SON p.Pro507Arg (c.1520C>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about SON p.Pro507Arg (c.1520C>G)?

AlphaMissense predicts ambiguous (score 0.4848) — an in-silico prediction, not a clinical call.

SON p.Pro507Arg

c.1520C>G · rs761928315 · VCV3248568

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4848 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

ZTTK syndrome

Computational evidence

Protein change
AlphaMissense	0.4848	ambiguous
REVEL	0.225	benign-leaning
SaProt	LLR -10.07	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 4.3, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 7,951 bp · p 0.32 · regional, not allelic
Overall
CADD	25.1	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 0.00223% East Asian · 1/44,882 alleles

Overall 0.000124% 2/1,614,146 alleles · very rare exomes 2/1,461,888 · genomes 0/152,258 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,882
South Asian	0.0011%	91,088

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.Pro507Arg
Coding: c.1520C>G
MANE Select: NM_138927
dbSNP: rs761928315
Type: single nucleotide variant
Location: chr21:33550751 (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 p.Pro507Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-pro507arg (accessed [today's date]).

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