# NM_003106.4(SOX2):c.36G>C (p.Pro12=)

https://sugi.bio/variant/sox2-p-pro12

## Summary

**SOX2 p.Pro12= (c.36G>C)** is classified **Uncertain significance** in SOX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-09). Very rare (popmax 0.00817%, afr); Associated with anophthalmia/microphthalmia-esophageal atresia syndrome.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.00817%, afr)

## For patients & families {#patients}

This is a change in the SOX2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to anophthalmia/microphthalmia-esophageal atresia syndrome.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0001443/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [SOX2](https://sugi.bio/atlas/gene/SOX2/) |
| Protein change (HGVS p.) | p.Pro12= |
| Coding change (HGVS c.) | c.36G>C |
| Variant type | single nucleotide variant |
| Location | chr3:181712396-181712396 (GRCh38) |
| ClinVar | [VCV3705509](https://www.ncbi.nlm.nih.gov/clinvar/variation/3705509/) |

**All HGVS expressions:** `LRG_719:g.5463G>C`, `LRG_719t1:c.36G>C`, `NC_000003.11:g.181430184G>C`, `NC_000003.12:g.181712396G>C`, `NG_009080.1:g.5463G>C`, `NG_051137.2:g.4649G>C`, `NM_003106.4:c.36G>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.889, GERP -3.05, phastCons 1 — weakly conserved position
- CADD: **PHRED 12.68**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.00817%** (afr) · FAF95 0.00353% · FAF99 0.00242% · 6/73,418 in the highest group · 12/1,577,012 alleles overall — very rare (popmax 0.00817%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00817% | 12,236 |
| East Asian | 0.00704% | 14,200 |
| Remaining individuals (not grpmax-eligible) | 0.00164% | 60,960 |
| South Asian | 0.00114% | 88,062 |
| European (non-Finnish) | 8.6e-05% | 1,162,156 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-09.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-09 |

## Associated conditions {#conditions}

[anophthalmia/microphthalmia-esophageal atresia syndrome](https://sugi.bio/atlas/disease/anophthalmia-microphthalmia-esophageal-atresia-syndrome/).

**Reported phenotype names (ClinVar):** Anophthalmia/microphthalmia-esophageal atresia syndrome, AEG SYNDROME, SOX2 Disorder, MICROPHTHALMIA AND ESOPHAGEAL ATRESIA SYNDROME.

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3705509). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*