Is SOX9 p.Pro307Arg (c.920C>G) pathogenic?

SOX9 p.Pro307Arg (c.920C>G) is classified Conflicting classifications of pathogenicity in SOX9 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-10). AlphaMissense: ambiguous (0.5016); Rare (popmax 0.676%, mid); Associated with campomelic dysplasia.

What condition is associated with SOX9 p.Pro307Arg (c.920C>G)?

SOX9 p.Pro307Arg (c.920C>G) is associated with campomelic dysplasia (ClinVar).

How common is SOX9 p.Pro307Arg (c.920C>G) in the general population?

SOX9 p.Pro307Arg (c.920C>G) is rare (popmax 0.676%, mid) (gnomAD).

What do computational predictors say about SOX9 p.Pro307Arg (c.920C>G)?

AlphaMissense predicts ambiguous (score 0.5016) — an in-silico prediction, not a clinical call.

SOX9 p.Pro307Arg

c.920C>G · rs202028563 · VCV1375451

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5016 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.676%, mid)

Conditions

campomelic dysplasia

Computational evidence

Protein change
AlphaMissense	0.5016	ambiguous
REVEL	0.426	indeterminate
SaProt	LLR -9.26	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP 0.77, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 794 bp · p 0.053 · regional, not allelic
Overall
CADD	24.7	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 0.676% Middle Eastern · 41/6,062 alleles

Filtering AF 0.512% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.455%

Overall 0.00446% 72/1,613,122 alleles · rare exomes 58/1,460,840 · genomes 14/152,282 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.676%	148
Admixed American	0.025%	4,001
Remaining individualsnot grpmax-eligible	0.0112%	8,925
African / African-American	0.00133%	75,068
European (non-Finnish)	0.000678%	147,485

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: SOX9
Protein: p.Pro307Arg
Coding: c.920C>G
MANE Select: NM_000346
dbSNP: rs202028563
Type: single nucleotide variant
Location: chr17:72123777 (GRCh38)
Gene constraint: LOEUF 0.154 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.69 · 1 PDB
Residue 307: a UniProt-annotated variant site (in cmd1); the 'transactivation domain (tam)' region

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 p.Pro307Leu Uncertain significance ★ ⚠ same residue
SOX9 p.Pro307= Likely benign ★ same residue
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

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-pro307arg (accessed [today's date]).

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