Is SOX18 p.Pro201Ser (c.601C>T) pathogenic?

SOX18 p.Pro201Ser (c.601C>T) is classified Uncertain significance in SOX18 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-09). AlphaMissense: likely benign (0.0858); Ultra-rare (popmax 0.0503%, nfe); Associated with hypotrichosis-lymphedema-telangiectasia-renal defect syndrome.

How common is SOX18 p.Pro201Ser (c.601C>T) in the general population?

SOX18 p.Pro201Ser (c.601C>T) is ultra-rare (popmax 0.0503%, nfe) (gnomAD).

What do computational predictors say about SOX18 p.Pro201Ser (c.601C>T)?

AlphaMissense predicts likely benign (score 0.0858) — an in-silico prediction, not a clinical call.

SOX18 p.Pro201Ser

Q: What condition is associated with SOX18 p.Pro201Ser (c.601C>T)?

SOX18 p.Pro201Ser (c.601C>T) is associated with hypotrichosis-lymphedema-telangiectasia-renal defect syndrome, hypotrichosis-lymphedema-telangiectasia syndrome (ClinVar).

Q: How is Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.601C>T · rs1033865056 · VCV2148873

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0858 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0503%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypotrichosis-lymphedema-telangiectasia-renal defect syndrome

Computational evidence

Protein change
AlphaMissense	0.0858	likely benign
REVEL	0.275	benign-leaning
SaProt	LLR -7.00	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 8.2	GERP 1.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 1,347 bp · p 0.29 · regional, not allelic
Overall
CADD	23.4	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 0.0503% European (non-Finnish) · 540/1,072,684 alleles

Filtering AF 0.0468% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0454%

Overall 0.041% 563/1,374,230 alleles · ultra-rare exomes 533/1,222,300 · genomes 30/151,930 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0503%	1,986
Remaining individualsnot grpmax-eligible	0.0249%	4,022
Admixed American	0.0113%	8,883
African / African-American	0.0107%	9,333

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.Pro201Ser
Coding: c.601C>T
MANE Select: NM_018419
dbSNP: rs1033865056
Type: single nucleotide variant
Location: chr20:64048720 (GRCh38)
Gene constraint: LOEUF 1.483 · pLI 0.22 (gnomAD)
Structure: AlphaFold pLDDT 63.44
Residue 201: the 'disordered' region; the 'important for transcriptional activation' region

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

Disease context

hypotrichosis-lymphedema-telangiectasia-renal defect syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypotrichosis-lymphedema-telangiectasia syndrome

For Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

SOX18 p.Gln161Ter Pathogenic/Likely pathogenic ★★ same condition
SOX18 p.Ala162Glu Uncertain significance ★★ ⚠ same condition
SOX18 p.Ala229Val Uncertain significance ★★ ⚠ same condition
SOX18 p.Ala250Thr Uncertain significance ★★ ⚠ same condition
SOX18 p.Ala30Ser Uncertain significance ★★ ⚠ same condition
SOX18 p.Arg271Lys Uncertain significance ★★ ⚠ same condition
SOX18 p.Asp321Asn Uncertain significance ★★ same condition
SOX18 p.Gly222Arg 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/sox18-p-pro201ser (accessed [today's date]).

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