Is SON p.Ala847Pro (c.2539G>C) pathogenic?

SON p.Ala847Pro (c.2539G>C) is classified Uncertain significance in SON (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-12). AlphaMissense: likely pathogenic (0.9655); Very rare (popmax 0.00534%, afr); Associated with ZTTK syndrome.

What condition is associated with SON p.Ala847Pro (c.2539G>C)?

SON p.Ala847Pro (c.2539G>C) is associated with ZTTK syndrome (ClinVar).

How common is SON p.Ala847Pro (c.2539G>C) in the general population?

SON p.Ala847Pro (c.2539G>C) is very rare (popmax 0.00534%, afr) (gnomAD).

What do computational predictors say about SON p.Ala847Pro (c.2539G>C)?

AlphaMissense predicts likely pathogenic (score 0.9655) — an in-silico prediction, not a clinical call.

SON p.Ala847Pro

c.2539G>C · rs766258977 · VCV2436229

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9655 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

ZTTK syndrome

Computational evidence

Protein change
AlphaMissense	0.9655	likely pathogenic
REVEL	0.316	indeterminate
SaProt	LLR -12.75	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 4.5, phastCons 1
Regional constraint	o/e 0.41	unconstrained · MANE · 210 bp · p 1.7e-08 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,880 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000434% 7/1,613,090 alleles · very rare exomes 3/1,460,904 · genomes 4/152,186 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,720
Remaining individualsnot grpmax-eligible	0.00321%	31,198
European (non-Finnish)	8.47e-05%	1,180,040

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.Ala847Pro
Coding: c.2539G>C
MANE Select: NM_138927
dbSNP: rs766258977
Type: single nucleotide variant
Location: chr21:33551770 (GRCh38)
Gene constraint: LOEUF 0.051 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 36.48 · 4 PDB
Residue 847: the '17 x 10 aa tandem repeats of l-a-[st]-[nsg]-[ts]-mdsqm' 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.Arg1039His 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-ala847pro (accessed [today's date]).

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