Is SON p.Arg1998Trp (c.5992C>T) pathogenic?

SON p.Arg1998Trp (c.5992C>T) is classified Uncertain significance in SON (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-27). AlphaMissense: likely pathogenic (0.9258); Very rare (popmax 0.00222%, sas).

How common is SON p.Arg1998Trp (c.5992C>T) in the general population?

SON p.Arg1998Trp (c.5992C>T) is very rare (popmax 0.00222%, sas) (gnomAD).

What do computational predictors say about SON p.Arg1998Trp (c.5992C>T)?

AlphaMissense predicts likely pathogenic (score 0.9258) — an in-silico prediction, not a clinical call.

SON p.Arg1998Trp

c.5992C>T · rs752248601 · VCV1483947

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9258 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00222%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9258	likely pathogenic
REVEL	0.069	moderately benign-leaning
SaProt	LLR -11.79	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
Regional constraint	o/e 0.62	unconstrained · MANE · 2,181 bp · p 1.3e-08 · regional, not allelic
Overall
CADD	18.6	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 0.00222% South Asian · 2/90,160 alleles

Filtering AF 0.000368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000138%

Overall 0.000499% 8/1,604,506 alleles · very rare exomes 5/1,453,028 · genomes 3/151,478 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00222%	45,080
European (non-Finnish)	0.00051%	196,122

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.Arg1998Trp
Coding: c.5992C>T
MANE Select: NM_138927
dbSNP: rs752248601
Type: single nucleotide variant
Location: chr21:33555223 (GRCh38)
Gene constraint: LOEUF 0.051 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 36.48 · 4 PDB
Residue 1998: the 'disordered' region; the '2 x 19 aa repeats of p-s-r-r-r-r-s-r-s-v-v-r-r-r-s-f-s-i-s' region

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

Similar variants

SON p.Arg1998_Arg1999insSerArgThrProSerArgArg Likely benign ★★ same residue
SON p.Arg1998_Arg1999insSerArgThrProSerArgArgSerArgThrProSerArgArg Uncertain significance ★ 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

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-arg1998trp (accessed [today's date]).

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