Is SOX2 p.Pro304= (c.912C>T) pathogenic?

SOX2 p.Pro304= (c.912C>T) is classified Likely benign in SOX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-23). Ultra-rare (popmax 0.0165%, mid); Associated with anophthalmia/microphthalmia-esophageal atresia syndrome.

What condition is associated with SOX2 p.Pro304= (c.912C>T)?

SOX2 p.Pro304= (c.912C>T) is associated with anophthalmia/microphthalmia-esophageal atresia syndrome (ClinVar).

How common is SOX2 p.Pro304= (c.912C>T) in the general population?

SOX2 p.Pro304= (c.912C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

SOX2 p.Pro304=

c.912C>T · rs747668628 · VCV2075556

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

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 0.089	GERP -2.9, phastCons 0.89
Overall
CADD	9.83	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,070 alleles

Filtering AF 0.00144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000902%

Overall 0.00075% 12/1,600,318 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,070
South Asian	0.00446%	22,407
European (non-Finnish)	0.000596%	167,727

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.Pro304=
Coding: c.912C>T
MANE Select: NM_003106
dbSNP: rs747668628
Type: single nucleotide variant
Location: chr3:181713272 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.91 · 13 PDB
Residue 304: 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-pro304 (accessed [today's date]).

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