Is SOX2 p.Pro252= (c.756C>T) pathogenic?

SOX2 p.Pro252= (c.756C>T) is classified Uncertain significance in SOX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-26). Very rare (popmax 0.00934%, afr); Associated with anophthalmia/microphthalmia-esophageal atresia syndrome.

What condition is associated with SOX2 p.Pro252= (c.756C>T)?

SOX2 p.Pro252= (c.756C>T) is associated with anophthalmia/microphthalmia-esophageal atresia syndrome (ClinVar).

How common is SOX2 p.Pro252= (c.756C>T) in the general population?

SOX2 p.Pro252= (c.756C>T) is very rare (popmax 0.00934%, afr) (gnomAD).

SOX2 p.Pro252=

c.756C>T · VCV4776913

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

Conditions

anophthalmia/microphthalmia-esophageal atresia syndrome

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 0.11	GERP -2.8, phastCons 0.92
Overall
CADD	9.581	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00934% African / African-American · 7/74,934 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000496% 8/1,613,814 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00934%	10,705
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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: SOX2
Protein: p.Pro252=
Coding: c.756C>T
MANE Select: NM_003106
Type: single nucleotide variant
Location: chr3:181713116 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.91 · 13 PDB
Residue 252: the 'disordered' region

Full SOX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

anophthalmia/microphthalmia-esophageal atresia syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SOX2 p.Glu8Ter Pathogenic/Likely pathogenic ★★ same condition
SOX2 p.Tyr207Ter Pathogenic/Likely pathogenic ★★ same condition
SOX2 p.Gly142Arg Uncertain significance ★★ ⚠ same condition
SOX2 p.Pro264Thr Uncertain significance ★★ ⚠ same condition
SOX2 p.Thr26Ala Uncertain significance ★★ ⚠ same condition
SOX2 p.Ala281= Likely benign ★★ same condition
SOX2 p.Ala287= Benign/Likely benign ★★ same condition
SOX2 p.Asn164= 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/sox2-p-pro252 (accessed [today's date]).

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