Is SON p.Ile2033Val (c.6097A>G) pathogenic?

SON p.Ile2033Val (c.6097A>G) is classified Conflicting classifications of pathogenicity in SON (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-09). AlphaMissense: likely benign (0.1075); Ultra-rare (popmax 0.0269%, afr).

How common is SON p.Ile2033Val (c.6097A>G) in the general population?

SON p.Ile2033Val (c.6097A>G) is ultra-rare (popmax 0.0269%, afr) (gnomAD).

What do computational predictors say about SON p.Ile2033Val (c.6097A>G)?

AlphaMissense predicts likely benign (score 0.1075) — an in-silico prediction, not a clinical call.

SON p.Ile2033Val

c.6097A>G · rs376444685 · VCV1921854

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1075 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0269%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1075	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -5.53	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 2, phastCons 0.8
Regional constraint	o/e 0.62	unconstrained · MANE · 2,181 bp · p 1.3e-08 · regional, not allelic
Overall
CADD	13.18	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 0.0269% African / African-American · 20/74,364 alleles

Filtering AF 0.0178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0148%

Overall 0.00168% 27/1,603,352 alleles · ultra-rare exomes 11/1,451,040 · genomes 16/152,312 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0269%	3,718
Admixed American	0.00512%	19,525
Remaining individualsnot grpmax-eligible	0.00161%	62,058
European (non-Finnish)	0.000255%	391,701

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.Ile2033Val
Coding: c.6097A>G
MANE Select: NM_138927
dbSNP: rs376444685
Type: single nucleotide variant
Location: chr21:33555328 (GRCh38)
Gene constraint: LOEUF 0.051 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 36.48 · 4 PDB
Residue 2033: the 'disordered' region; the '3 x tandem repeats of [st]-p-[vli]-r-[rl]-[rk]-[rf]-s-r' region

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

Similar variants

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
SON c.6657+316G>A 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-ile2033val (accessed [today's date]).

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