Is SON p.Ser1856Phe (c.5567C>T) pathogenic?

SON p.Ser1856Phe (c.5567C>T) is classified Uncertain significance in SON (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-06). AlphaMissense: likely pathogenic (0.8484); Very rare (popmax 0.00267%, afr); Associated with SON-related disorder.

What condition is associated with SON p.Ser1856Phe (c.5567C>T)?

SON p.Ser1856Phe (c.5567C>T) is associated with SON-related disorder (ClinVar).

How common is SON p.Ser1856Phe (c.5567C>T) in the general population?

SON p.Ser1856Phe (c.5567C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about SON p.Ser1856Phe (c.5567C>T)?

AlphaMissense predicts likely pathogenic (score 0.8484) — an in-silico prediction, not a clinical call.

SON p.Ser1856Phe

c.5567C>T · rs1408233408 · VCV2632551

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8484 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SON-related disorder

Computational evidence

Protein change
AlphaMissense	0.8484	likely pathogenic
REVEL	0.248	benign-leaning
SaProt	LLR -11.18	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 4.2, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 2,223 bp · p 0.00022 · regional, not allelic
Overall
CADD	24.8	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 0.00267% African / African-American · 2/75,032 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,613,936 alleles · very rare exomes 3/1,461,656 · genomes 0/152,280 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,516
Remaining individualsnot grpmax-eligible	0.0016%	62,508

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.Ser1856Phe
Coding: c.5567C>T
MANE Select: NM_138927
dbSNP: rs1408233408
Type: single nucleotide variant
Location: chr21:33554798 (GRCh38)
Gene constraint: LOEUF 0.051 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 36.48 · 4 PDB
Residue 1856: the 'disordered' region

Full SON gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

SON-related disorder

Similar variants

SON p.Gln45Pro Uncertain significance ★★ ⚠ same condition
SON p.Leu1666Val Uncertain significance ★★ ⚠ same condition
SON p.Pro431His Uncertain significance ★★ ⚠ same condition
SON p.Ser609Leu Uncertain significance ★★ ⚠ same condition
SON p.Thr1382Ser Uncertain significance ★★ ⚠ same condition
SON p.Arg1956His Likely pathogenic ★ ⚠ same condition
SON p.Gln228Ter Likely pathogenic ★ same condition
SON p.Gln918Ter Pathogenic ★ 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-ser1856phe (accessed [today's date]).

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