Is SOX9 p.Pro404= (c.1212C>G) pathogenic?

SOX9 p.Pro404= (c.1212C>G) is classified Likely benign in SOX9 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-06-17). Very rare (popmax 0.00667%, amr); Associated with SOX9-related disorder.

What condition is associated with SOX9 p.Pro404= (c.1212C>G)?

SOX9 p.Pro404= (c.1212C>G) is associated with SOX9-related disorder (ClinVar).

How common is SOX9 p.Pro404= (c.1212C>G) in the general population?

SOX9 p.Pro404= (c.1212C>G) is very rare (popmax 0.00667%, amr) (gnomAD).

SOX9 p.Pro404=

c.1212C>G · rs749575769 · VCV3036514

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Conditions

SOX9-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.85	GERP -0.31, phastCons 1
Overall
CADD	11.47	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/59,992 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00031% 5/1,613,370 alleles · very rare exomes 4/1,461,216 · genomes 1/152,154 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	14,998
European (non-Finnish)	8.48e-05%	1,179,807

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.Pro404=
Coding: c.1212C>G
MANE Select: NM_000346
dbSNP: rs749575769
Type: single nucleotide variant
Location: chr17:72124069 (GRCh38)
Gene constraint: LOEUF 0.154 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 56.69 · 1 PDB
Residue 404: a UniProt-annotated variant site (in cmd1); the 'disordered' region; the 'transactivation domain (tac)' region

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

Disease context

SOX9-related disorder

Similar variants

SOX9 p.Pro176Ser Likely pathogenic ★★ same condition
SOX9 p.Arg264Ter Likely pathogenic ★ same condition
SOX9 p.Pro176Thr Likely pathogenic ★ same condition
SOX9 p.Tyr452Ter Likely pathogenic ★ same condition
SOX9 p.Glu194Gly Uncertain significance ★ ⚠ same condition
SOX9 p.Arg177Pro Uncertain significance ⚠ same condition
SOX9 p.Gly263= Likely benign same condition
SRA1 c.26-64C>T Likely benign 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-pro404 (accessed [today's date]).

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