Is SOX2 p.Pro221Arg (c.662C>G) pathogenic?

SOX2 p.Pro221Arg (c.662C>G) is classified Uncertain significance in SOX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-01). AlphaMissense: likely pathogenic (0.8388); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SOX2 p.Pro221Arg (c.662C>G)?

SOX2 p.Pro221Arg (c.662C>G) is associated with Inborn genetic diseases (ClinVar).

How common is SOX2 p.Pro221Arg (c.662C>G) in the general population?

SOX2 p.Pro221Arg (c.662C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SOX2 p.Pro221Arg (c.662C>G)?

AlphaMissense predicts likely pathogenic (score 0.8388) — an in-silico prediction, not a clinical call.

SOX2 p.Pro221Arg

c.662C>G · rs2473719643 · VCV2331561

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8388 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8388	likely pathogenic
REVEL	0.795	moderately pathogenic-leaning
SaProt	LLR -9.30	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 604 bp · p 4.6e-05 · regional, not allelic
Overall
CADD	33.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SOX2
Protein: p.Pro221Arg
Coding: c.662C>G
MANE Select: NM_003106
dbSNP: rs2473719643
Type: single nucleotide variant
Location: chr3:181713022 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.91 · 13 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SOX2 p.Pro221Ser Uncertain significance ★ ⚠ same residue
SOX2 p.Pro264Thr Uncertain significance ★★ ⚠ same condition
SOX2 p.Val202Met Uncertain significance ★★ ⚠ same condition
SOX2 p.Ala191Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
SOX2 p.Ala287Thr Uncertain significance ★ ⚠ same condition
SOX2 p.Gln299His Uncertain significance ★ ⚠ same condition
SOX2 p.Gly190Ser Uncertain significance ★ ⚠ same condition
SOX2 p.Gly241Ser 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/sox2-p-pro221arg (accessed [today's date]).

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