Is SOX4 p.Ser333Pro (c.997T>C) pathogenic?

SOX4 p.Ser333Pro (c.997T>C) is classified Uncertain significance in SOX4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-11). AlphaMissense: likely benign (0.0738); Very rare (popmax 0.00994%, eas); Associated with Inborn genetic diseases.

What condition is associated with SOX4 p.Ser333Pro (c.997T>C)?

SOX4 p.Ser333Pro (c.997T>C) is associated with Inborn genetic diseases (ClinVar).

How common is SOX4 p.Ser333Pro (c.997T>C) in the general population?

SOX4 p.Ser333Pro (c.997T>C) is very rare (popmax 0.00994%, eas) (gnomAD).

What do computational predictors say about SOX4 p.Ser333Pro (c.997T>C)?

AlphaMissense predicts likely benign (score 0.0738) — an in-silico prediction, not a clinical call.

SOX4 p.Ser333Pro

c.997T>C · rs752979777 · VCV3167793

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0738 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00994%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0738	likely benign
REVEL	0.237	benign-leaning
SaProt	LLR -7.27	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 0.69, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 1,022 bp · p 0.058 · regional, not allelic
Overall
CADD	19.81	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00994% East Asian · 3/30,196 alleles

Filtering AF 0.00263% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00143%

Overall 0.00037% 4/1,082,078 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00994%	10,065
European (non-Finnish)	0.000101%	985,523

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: SOX4
Protein: p.Ser333Pro
Coding: c.997T>C
MANE Select: NM_003107
dbSNP: rs752979777
Type: single nucleotide variant
Location: chr6:21595531 (GRCh38)
Gene constraint: LOEUF 0.72 · pLI 0.79 (gnomAD)
Structure: AlphaFold pLDDT 55.71
Residue 333: the 'disordered' region

Full SOX4 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

Similar variants

SOX4 p.Ser333Ala Uncertain significance ★ ⚠ same residue
SOX4 p.Ser333Ter Likely pathogenic ★ same residue
SOX4 p.Ala145Thr Uncertain significance ★★ ⚠ same condition
SOX4 p.Ala253Val Uncertain significance ★★ ⚠ same condition
SOX4 p.Arg110Pro Uncertain significance ★★ ⚠ same condition
SOX4 p.Gly226Ser Uncertain significance ★★ ⚠ same condition
SOX4 p.Leu100Phe Uncertain significance ★★ ⚠ same condition
SOX4 p.Pro214Ser Uncertain significance ★★ ⚠ 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/sox4-p-ser333pro (accessed [today's date]).

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