Is SOX9 p.Pro153Ser (c.457C>T) pathogenic?

SOX9 p.Pro153Ser (c.457C>T) is classified Uncertain significance in SOX9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-11). AlphaMissense: likely pathogenic (0.9998); Absent from gnomAD v4.1; Associated with campomelic dysplasia.

What condition is associated with SOX9 p.Pro153Ser (c.457C>T)?

SOX9 p.Pro153Ser (c.457C>T) is associated with campomelic dysplasia (ClinVar).

How common is SOX9 p.Pro153Ser (c.457C>T) in the general population?

SOX9 p.Pro153Ser (c.457C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SOX9 p.Pro153Ser (c.457C>T)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

SOX9 p.Pro153Ser

c.457C>T · VCV4855982

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

campomelic dysplasia

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic · top 8% in SOX9
REVEL	0.927	moderately pathogenic-leaning
SaProt	LLR -13.30	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 2.2, phastCons 1
Regional constraint	o/e 0.29	constrained · MANE · 1,059 bp · p 8.8e-10 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SOX9
Protein: p.Pro153Ser
Coding: c.457C>T
MANE Select: NM_000346
Type: single nucleotide variant
Location: chr17:72122744 (GRCh38)
Gene constraint: LOEUF 0.154 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.69 · 1 PDB
Residue 153: a DNA-binding region; a UniProt-annotated variant site (in cmd1); an α-helix

Full SOX9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

campomelic dysplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SOX9 c.432-2A>T Pathogenic ★★ same condition
SOX9 p.Ala158Val Pathogenic/Likely pathogenic ★★ same condition
SOX9 p.Arg152Pro Pathogenic/Likely pathogenic ★★ same condition
SOX9 p.Arg394Ter Pathogenic ★★ same condition
SOX9 p.Gln340Ter Pathogenic/Likely pathogenic ★★ same condition
SOX9 p.Gln357Ter Pathogenic ★★ same condition
SOX9 p.Glu148Ter Pathogenic ★★ same condition
SOX9 p.Pro170Ala Likely 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/sox9-p-pro153ser (accessed [today's date]).

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