Is SOX4 p.Pro337Arg (c.1010C>G) pathogenic?

SOX4 p.Pro337Arg (c.1010C>G) is classified Uncertain significance in SOX4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-08). AlphaMissense: likely benign (0.1018); Very rare (popmax 0.00451%, nfe); Associated with Inborn genetic diseases.

What condition is associated with SOX4 p.Pro337Arg (c.1010C>G)?

SOX4 p.Pro337Arg (c.1010C>G) is associated with Inborn genetic diseases (ClinVar).

How common is SOX4 p.Pro337Arg (c.1010C>G) in the general population?

SOX4 p.Pro337Arg (c.1010C>G) is very rare (popmax 0.00451%, nfe) (gnomAD).

What do computational predictors say about SOX4 p.Pro337Arg (c.1010C>G)?

AlphaMissense predicts likely benign (score 0.1018) — an in-silico prediction, not a clinical call.

SOX4 p.Pro337Arg

c.1010C>G · rs755703012 · VCV3167774

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1018 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00451%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1018	likely benign
REVEL	0.214	benign-leaning
SaProt	LLR -5.77	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.7	GERP -0.11, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 1,022 bp · p 0.058 · regional, not allelic
Overall
CADD	22.3	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 0.00451% European (non-Finnish) · 44/976,068 alleles

Filtering AF 0.00342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00304%

Overall 0.00379% 46/1,212,760 alleles · very rare exomes 44/1,063,014 · genomes 2/149,746 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00455%	21,965
European (non-Finnish)grpmax	0.00451%	22,183

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro337Arg
Coding: c.1010C>G
MANE Select: NM_003107
dbSNP: rs755703012
Type: single nucleotide variant
Location: chr6:21595544 (GRCh38)
Gene constraint: LOEUF 0.72 · pLI 0.79 (gnomAD)
Structure: AlphaFold pLDDT 55.71
Residue 337: 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.Pro337= Likely benign ★ 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
SOX4 p.Ser32Ala 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-pro337arg (accessed [today's date]).

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