Is GSX2 p.Ser52= (c.156C>T) pathogenic?

GSX2 p.Ser52= (c.156C>T) is classified Benign in GSX2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-08-10). Common (popmax 82.6%, eas) — too common for a highly-penetrant pathogenic allele; Associated with diencephalic-mesencephalic junction dysplasia syndrome 2.

What condition is associated with GSX2 p.Ser52= (c.156C>T)?

GSX2 p.Ser52= (c.156C>T) is associated with diencephalic-mesencephalic junction dysplasia syndrome 2 (ClinVar).

GSX2 p.Ser52=

Q: How common is GSX2 p.Ser52= (c.156C>T) in the general population?

GSX2 p.Ser52= (c.156C>T) is common (popmax 82.6%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.156C>T · rs3194383 · VCV1182813

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 82.6%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

diencephalic-mesencephalic junction dysplasia syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.8	GERP -3.1, phastCons 1
Overall
CADD	12.15	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 82.6% East Asian · 36,975/44,780 alleles

Filtering AF 81.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 81.6%

Overall 61.7% 995,388/1,613,098 alleles · common exomes 911,193/1,461,164 · genomes 84,195/151,934 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	82.6%	1
Amishnot grpmax-eligible	73.8%	1
Admixed American	73.8%	1
Finnishnot grpmax-eligible	64.7%	2
South Asian	63.7%	2
European (non-Finnish)	62%	2
Remaining individualsnot grpmax-eligible	61.7%	2
Middle Eastern	57.8%	2
Ashkenazi Jewishnot grpmax-eligible	55.5%	2
African / African-American	33.4%	3

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: GSX2
Protein: p.Ser52=
Coding: c.156C>T
MANE Select: NM_133267
dbSNP: rs3194383
Type: single nucleotide variant
Location: chr4:54100500 (GRCh38)
Gene constraint: LOEUF 1.278 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.18
Residue 52: a UniProt-annotated variant site (in dmjds2; loss of protein expression)

Full GSX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

diencephalic-mesencephalic junction dysplasia syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GSX2 p.Gly107Ser Benign ★★ same condition
GSX2 p.His136= Benign ★★ same condition
GSX2 c.574+129C>T Benign ★★ same type
GSX2 c.575-40C>A Benign ★★ same type
GSX2 p.Ala116Thr Uncertain significance ★ ⚠ same type
GSX2 p.Ala148Val Uncertain significance ★ ⚠ same type
GSX2 p.Ala161Thr Uncertain significance ★ ⚠ same type
GSX2 p.Ala282Thr 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/gsx2-p-ser52 (accessed [today's date]).

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