Is SOX2 p.Ser259fs (c.775_778del) pathogenic?

SOX2 p.Ser259fs (c.775778del) is classified Likely pathogenic in SOX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-02). Absent from gnomAD; Associated with anophthalmia/microphthalmia-esophageal atresia syndrome.

What condition is associated with SOX2 p.Ser259fs (c.775_778del)?

SOX2 p.Ser259fs (c.775_778del) is associated with anophthalmia/microphthalmia-esophageal atresia syndrome (ClinVar).

How common is SOX2 p.Ser259fs (c.775_778del) in the general population?

SOX2 p.Ser259fs (c.775_778del) is absent from gnomAD (gnomAD).

SOX2 p.Ser259fs

c.775_778del · rs2473720054 · VCV3235168

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

anophthalmia/microphthalmia-esophageal atresia syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon in the last exon (1 of 1) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.1	GERP 2.3, phastCons 1
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SOX2
Protein: p.Ser259fs
Coding: c.775_778del
MANE Select: NM_003106
dbSNP: rs2473720054
Type: Deletion
Location: chr3:181713133 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.91 · 13 PDB
Residue 259: 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.Glu8_Leu9insTer Pathogenic ★ same condition
SOX2 p.Phe48del Pathogenic ★ same condition
SOX2 p.Pro181fs Pathogenic ★ same condition
SOX2 p.Pro253fs Likely pathogenic ★ same condition
SOX2 p.Gly20fs Pathogenic same condition
SOX2 p.Gly280fs Pathogenic same condition
SOX2 p.Met1fs Pathogenic same condition
SOX2 p.Met276fs Pathogenic 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-ser259fs (accessed [today's date]).

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