Is SOX9 p.Pro367Ala (c.1099C>G) pathogenic?

SOX9 p.Pro367Ala (c.1099C>G) is classified Conflicting classifications of pathogenicity in SOX9 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-27). AlphaMissense: likely benign (0.054); Ultra-rare (popmax 0.034%, amr); Associated with Inborn genetic diseases.

What condition is associated with SOX9 p.Pro367Ala (c.1099C>G)?

SOX9 p.Pro367Ala (c.1099C>G) is associated with Inborn genetic diseases, campomelic dysplasia (ClinVar).

How common is SOX9 p.Pro367Ala (c.1099C>G) in the general population?

SOX9 p.Pro367Ala (c.1099C>G) is ultra-rare (popmax 0.034%, amr) (gnomAD).

What do computational predictors say about SOX9 p.Pro367Ala (c.1099C>G)?

AlphaMissense predicts likely benign (score 0.054) — an in-silico prediction, not a clinical call.

SOX9 p.Pro367Ala

c.1099C>G · rs542727010 · VCV2081422

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.054 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.034%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.054	likely benign
REVEL	0.357	indeterminate
SaProt	LLR -8.07	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP 1.4, phastCons 0.88
Regional constraint	o/e 0.90	unconstrained · MANE · 794 bp · p 0.053 · regional, not allelic
Overall
CADD	13.95	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 0.034% Admixed American · 15/44,152 alleles

Filtering AF 0.0209% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0169%

Overall 0.0011% 16/1,450,536 alleles · ultra-rare exomes 14/1,299,184 · genomes 2/151,352 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.034%	2,943
European (non-Finnish)	9.05e-05%	1,104,481

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.Pro367Ala
Coding: c.1099C>G
MANE Select: NM_000346
dbSNP: rs542727010
Type: single nucleotide variant
Location: chr17:72123956 (GRCh38)
Gene constraint: LOEUF 0.154 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.69 · 1 PDB
Residue 367: a UniProt-annotated variant site (in cmd1); the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: campomelic dysplasia

Similar variants

SOX9 p.Pro367Arg Uncertain significance ★ ⚠ same residue
SOX9 p.Pro367Ser Uncertain significance ★ ⚠ 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-pro367ala (accessed [today's date]).

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