Is SON p.Ser1595Pro (c.4783T>C) pathogenic?

SON p.Ser1595Pro (c.4783T>C) is classified Conflicting classifications of pathogenicity in SON (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-01). AlphaMissense: likely benign (0.0999); Ultra-rare (popmax 0.0141%, nfe); Associated with ZTTK syndrome.

What condition is associated with SON p.Ser1595Pro (c.4783T>C)?

SON p.Ser1595Pro (c.4783T>C) is associated with ZTTK syndrome (ClinVar).

How common is SON p.Ser1595Pro (c.4783T>C) in the general population?

SON p.Ser1595Pro (c.4783T>C) is ultra-rare (popmax 0.0141%, nfe) (gnomAD).

What do computational predictors say about SON p.Ser1595Pro (c.4783T>C)?

AlphaMissense predicts likely benign (score 0.0999) — an in-silico prediction, not a clinical call.

SON p.Ser1595Pro

c.4783T>C · rs746252717 · VCV1351671

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0999 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0141%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ZTTK syndrome

Computational evidence

Protein change
AlphaMissense	0.0999	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -7.54	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 1.4	GERP 0.7, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 2,223 bp · p 0.00022 · regional, not allelic
Overall
CADD	16.37	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 0.0141% European (non-Finnish) · 166/1,180,016 alleles

Filtering AF 0.0123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0116%

Overall 0.0107% 172/1,614,038 alleles · ultra-rare exomes 168/1,461,850 · genomes 4/152,188 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0141%	7,109
Remaining individualsnot grpmax-eligible	0.008%	12,496
African / African-American	0.00133%	74,926

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.Ser1595Pro
Coding: c.4783T>C
MANE Select: NM_138927
dbSNP: rs746252717
Type: single nucleotide variant
Location: chr21:33554014 (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-ser1595pro (accessed [today's date]).

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