Is DSG2 c.523+252A>G pathogenic?

DSG2 c.523+252A>G is classified Benign in DSG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-06-18). Common (popmax 30.6%, eas) — too common for a highly-penetrant pathogenic allele.

DSG2 c.523+252A>G

Q: How common is DSG2 c.523+252A>G in the general population?

DSG2 c.523+252A>G is common (popmax 30.6%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

rs62095191 · VCV683845

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 30.6%, eas) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +252	deep intronic (+252 nt into the intron)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.54
Non-coding constraint	Z 2.22	1 kb window · o/e 0.82 · regional · uncalibrated
Overall
CADD	1.497	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 30.6% East Asian · 1,579/5,166 alleles

Filtering AF 29.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 28.8%

Overall 23% 34,931/151,970 alleles · common

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	34.6%	3
East Asiangrpmax	30.6%	3
Admixed American	29.2%	3
European (non-Finnish)	26.4%	4
Remaining individualsnot grpmax-eligible	23.4%	4
South Asian	22.1%	5
Middle Eastern	18.4%	5
Ashkenazi Jewishnot grpmax-eligible	17.5%	6
Amishnot grpmax-eligible	16%	6
African / African-American	12%	8

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: DSG2
Coding: c.523+252A>G
MANE Select: NM_001943
dbSNP: rs62095191
Type: single nucleotide variant
Location: chr18:31521495 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB

Full DSG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DSG2 c.1423+1G>T Likely pathogenic ★★ same type
DSG2 c.1424-1G>A Likely pathogenic ★★ same type
DSG2 c.523+1G>T Pathogenic/Likely pathogenic ★★ same type
DSG2 c.690+1G>A Pathogenic ★★ same type
DSG2 c.81+1G>T Likely pathogenic ★★ same type
DSG2 c.829-2A>T Likely pathogenic ★★ same type
DSG2 p.Arg46Gln Pathogenic/Likely pathogenic ★★ same type
DSG2 p.Arg46Trp Pathogenic/Likely pathogenic ★★ 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/dsg2-c-523-plus-252a-g (accessed [today's date]).

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