Is SON p.Ser700Pro (c.2098T>C) pathogenic?

SON p.Ser700Pro (c.2098T>C) is classified Conflicting classifications of pathogenicity in SON (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-07-27). AlphaMissense: likely pathogenic (0.5746); Very rare (popmax 0.000763%, nfe); Associated with SON-related disorder.

What condition is associated with SON p.Ser700Pro (c.2098T>C)?

SON p.Ser700Pro (c.2098T>C) is associated with SON-related disorder (ClinVar).

How common is SON p.Ser700Pro (c.2098T>C) in the general population?

SON p.Ser700Pro (c.2098T>C) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about SON p.Ser700Pro (c.2098T>C)?

AlphaMissense predicts likely pathogenic (score 0.5746) — an in-silico prediction, not a clinical call.

SON p.Ser700Pro

c.2098T>C · rs2085778381 · VCV2421204

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5746 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SON-related disorder

Computational evidence

Protein change
AlphaMissense	0.5746	likely pathogenic
REVEL	0.139	moderately benign-leaning
SaProt	LLR -6.76	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 3.4, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 447 bp · p 0.4 · regional, not allelic
Overall
CADD	23.1	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 0.000763% European (non-Finnish) · 9/1,179,990 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,613,988 alleles · very rare exomes 8/1,461,844 · genomes 1/152,144 · joint denominator

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.Ser700Pro
Coding: c.2098T>C
MANE Select: NM_138927
dbSNP: rs2085778381
Type: single nucleotide variant
Location: chr21:33551329 (GRCh38)
Gene constraint: LOEUF 0.051 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 36.48 · 4 PDB

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-ser700pro (accessed [today's date]).

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