Is SOX2 p.Pro253Ala (c.757C>G) pathogenic?

SOX2 p.Pro253Ala (c.757C>G) is classified Uncertain significance in SOX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-07-09). AlphaMissense: likely benign (0.1463); Very rare (popmax 0.00133%, afr).

How common is SOX2 p.Pro253Ala (c.757C>G) in the general population?

SOX2 p.Pro253Ala (c.757C>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about SOX2 p.Pro253Ala (c.757C>G)?

AlphaMissense predicts likely benign (score 0.1463) — an in-silico prediction, not a clinical call.

SOX2 p.Pro253Ala

c.757C>G · rs1034815541 · VCV1302955

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1463 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1463	likely benign
REVEL	0.401	indeterminate
SaProt	LLR -7.06	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 604 bp · p 4.6e-05 · regional, not allelic
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,056 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000929% 15/1,613,896 alleles · very rare exomes 13/1,461,602 · genomes 2/152,294 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,056
European (non-Finnish)	0.00119%	84,288

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.Pro253Ala
Coding: c.757C>G
MANE Select: NM_003106
dbSNP: rs1034815541
Type: single nucleotide variant
Location: chr3:181713117 (GRCh38)
Gene constraint: LOEUF 0.302 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.91 · 13 PDB
Residue 253: the 'disordered' region

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

Similar variants

SOX2 p.Pro253fs Likely pathogenic ★ same residue
SOX2 p.Glu8Ter Pathogenic/Likely pathogenic ★★ same type
SOX2 p.Tyr207Ter Pathogenic/Likely pathogenic ★★ same type
SOX2 p.Gly142Arg Uncertain significance ★★ ⚠ same type
SOX2 p.Pro264Thr Uncertain significance ★★ ⚠ same type
SOX2 p.Thr26Ala Uncertain significance ★★ ⚠ same type
SOX2 p.Val202Met Uncertain significance ★★ ⚠ same type
SOX2 c.*469C>A Benign ★★ same type

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-pro253ala (accessed [today's date]).

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