Is SOX3 p.Arg5Pro (c.14G>C) pathogenic?

SOX3 p.Arg5Pro (c.14G>C) is classified Conflicting classifications of pathogenicity in SOX3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-03-11). AlphaMissense: likely benign (0.0864); Ultra-rare (popmax 0.0154%, amr); Associated with intellectual disability, X-linked, with panhypopituitarism.

What condition is associated with SOX3 p.Arg5Pro (c.14G>C)?

SOX3 p.Arg5Pro (c.14G>C) is associated with intellectual disability, X-linked, with panhypopituitarism (ClinVar).

How common is SOX3 p.Arg5Pro (c.14G>C) in the general population?

SOX3 p.Arg5Pro (c.14G>C) is ultra-rare (popmax 0.0154%, amr) (gnomAD).

What do computational predictors say about SOX3 p.Arg5Pro (c.14G>C)?

AlphaMissense predicts likely benign (score 0.0864) — an in-silico prediction, not a clinical call.

SOX3 p.Arg5Pro

c.14G>C · rs112180170 · VCV804090

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0864 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, X-linked, with panhypopituitarism

Computational evidence

Protein change
AlphaMissense	0.0864	likely benign
REVEL	0.26	benign-leaning
SaProt	LLR -6.50	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 -2.4	GERP -2.6
Regional constraint	o/e 1.29	unconstrained · MANE · 155 bp · p 0.054 · regional, not allelic
Overall
CADD	1.689	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 0.0154% Admixed American · 7/45,568 alleles

Filtering AF 0.00716% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00508%

Overall 0.0044% 53/1,203,951 alleles · ultra-rare exomes 49/1,091,771 · genomes 4/112,180 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0154%	6,510
Remaining individualsnot grpmax-eligible	0.00633%	15,786
European (non-Finnish)	0.00482%	20,751

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: SOX3
Protein: p.Arg5Pro
Coding: c.14G>C
MANE Select: NM_005634
dbSNP: rs112180170
Type: single nucleotide variant
Location: chrX:140505047 (GRCh38)
Structure: AlphaFold pLDDT 58.40

Full SOX3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability, X-linked, with panhypopituitarism — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SOX3 p.Ala113Thr Uncertain significance ★★ ⚠ same condition
SOX3 p.Asn7Ser Uncertain significance ★★ ⚠ same condition
SOX3 p.Ala111Thr Uncertain significance ★ ⚠ same condition
SOX3 p.Arg422His Uncertain significance ★ ⚠ same condition
SOX3 p.Gly316Ser Conflicting classifications of pathogenicity ★ ⚠ same condition
SOX3 p.Val264Gly Uncertain significance ★ same condition
SOX3 p.Ser150Tyr Likely pathogenic same condition
SOX3 p.Ala248dup 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/sox3-p-arg5pro (accessed [today's date]).

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