Is SOX18 p.Pro71Ala (c.211C>G) pathogenic?

SOX18 p.Pro71Ala (c.211C>G) is classified Uncertain significance in SOX18 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-19). AlphaMissense: likely benign (0.0547); Very rare (popmax 0.00197%, amr).

How common is SOX18 p.Pro71Ala (c.211C>G) in the general population?

SOX18 p.Pro71Ala (c.211C>G) is very rare (popmax 0.00197%, amr) (gnomAD).

What do computational predictors say about SOX18 p.Pro71Ala (c.211C>G)?

AlphaMissense predicts likely benign (score 0.0547) — an in-silico prediction, not a clinical call.

SOX18 p.Pro71Ala

c.211C>G · VCV4781941

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0547 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00197%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0547	likely benign
REVEL	0.178	moderately benign-leaning
SaProt	LLR -6.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP -3.2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 1,347 bp · p 0.29 · regional, not allelic
Overall
CADD	14.14	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 0.00197% Admixed American · 1/50,814 alleles

Overall 0.000151% 2/1,325,774 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00197%	50,814
Remaining individualsnot grpmax-eligible	0.00185%	54,188

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: SOX18
Protein: p.Pro71Ala
Coding: c.211C>G
MANE Select: NM_018419
Type: single nucleotide variant
Location: chr20:64049306 (GRCh38)
Gene constraint: LOEUF 1.483 · pLI 0.22 (gnomAD)
Structure: AlphaFold pLDDT 63.44
Residue 71: the 'disordered' region

Full SOX18 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SOX18 p.Gln161Ter Pathogenic/Likely pathogenic ★★ same type
SOX18 p.Ala162Glu Uncertain significance ★★ ⚠ same type
SOX18 p.Ala229Val Uncertain significance ★★ ⚠ same type
SOX18 p.Ala250Thr Uncertain significance ★★ ⚠ same type
SOX18 p.Ala30Ser Uncertain significance ★★ ⚠ same type
SOX18 p.Arg140Leu Uncertain significance ★★ ⚠ same type
SOX18 p.Arg271Lys Uncertain significance ★★ ⚠ same type
SOX18 p.Asp13Asn Uncertain significance ★★ ⚠ 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/sox18-p-pro71ala (accessed [today's date]).

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