Is SON p.Arg1891Cys (c.5671C>T) pathogenic?

SON p.Arg1891Cys (c.5671C>T) is classified Uncertain significance in SON (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-14). AlphaMissense: likely pathogenic (0.8658); Ultra-rare (popmax 0.0329%, mid).

How common is SON p.Arg1891Cys (c.5671C>T) in the general population?

SON p.Arg1891Cys (c.5671C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about SON p.Arg1891Cys (c.5671C>T)?

AlphaMissense predicts likely pathogenic (score 0.8658) — an in-silico prediction, not a clinical call.

SON p.Arg1891Cys

c.5671C>T · rs756059870 · VCV3015689

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8658 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8658	likely pathogenic
REVEL	0.224	benign-leaning
SaProt	LLR -12.21	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 6	GERP 3.3, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 2,223 bp · p 0.00022 · regional, not allelic
Overall
CADD	26.6	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.000868% 14/1,613,780 alleles · ultra-rare exomes 10/1,461,838 · genomes 4/151,942 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
African / African-American	0.00401%	24,940
South Asian	0.0011%	91,080
European (non-Finnish)	0.000678%	147,499

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.Arg1891Cys
Coding: c.5671C>T
MANE Select: NM_138927
dbSNP: rs756059870
Type: single nucleotide variant
Location: chr21:33554902 (GRCh38)
Gene constraint: LOEUF 0.051 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 36.48 · 4 PDB
Residue 1891: the 'disordered' region

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

Similar variants

SON p.Arg1891His Likely benign ★ ⚠ same residue
SON c.6321+1G>A Pathogenic ★★ same type
SON p.Arg1081Ter Pathogenic ★★ same type
SON p.Arg1112Ter Pathogenic ★★ same type
SON p.Arg1825Ter Pathogenic ★★ same type
SON p.Arg2008Ter Pathogenic ★★ same type
SON p.Gln96Ter Pathogenic/Likely pathogenic ★★ same type
SON c.6657+160A>C Uncertain significance ★★ same type

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-arg1891cys (accessed [today's date]).

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