Is SON p.Pro1658Ser (c.4972C>T) pathogenic?

SON p.Pro1658Ser (c.4972C>T) is classified Uncertain significance in SON (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-02-10). AlphaMissense: likely pathogenic (0.6863); Ultra-rare (popmax 0.033%, mid); Associated with ZTTK syndrome.

What condition is associated with SON p.Pro1658Ser (c.4972C>T)?

SON p.Pro1658Ser (c.4972C>T) is associated with ZTTK syndrome (ClinVar).

How common is SON p.Pro1658Ser (c.4972C>T) in the general population?

SON p.Pro1658Ser (c.4972C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about SON p.Pro1658Ser (c.4972C>T)?

AlphaMissense predicts likely pathogenic (score 0.6863) — an in-silico prediction, not a clinical call.

SON p.Pro1658Ser

c.4972C>T · rs2085897193 · VCV1030015

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6863 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ZTTK syndrome

Computational evidence

Protein change
AlphaMissense	0.6863	likely pathogenic
REVEL	0.151	moderately benign-leaning
SaProt	LLR -6.32	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 4.5, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 2,223 bp · p 0.00022 · regional, not allelic
Overall
CADD	24.7	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 0.033% Middle Eastern · 2/6,060 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000124% 2/1,614,072 alleles · ultra-rare exomes 2/1,461,766 · genomes 0/152,306 · joint denominator

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.Pro1658Ser
Coding: c.4972C>T
MANE Select: NM_138927
dbSNP: rs2085897193
Type: single nucleotide variant
Location: chr21:33554203 (GRCh38)
Gene constraint: LOEUF 0.051 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 36.48 · 4 PDB
Residue 1658: the 'disordered' region

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-pro1658ser (accessed [today's date]).

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