Is DDB2 p.Thr246= (c.738G>A) pathogenic?

DDB2 p.Thr246= (c.738G>A) is classified Benign/Likely benign in DDB2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-04-01). Rare (popmax 0.86%, amr); Associated with xeroderma pigmentosum group E.

What condition is associated with DDB2 p.Thr246= (c.738G>A)?

DDB2 p.Thr246= (c.738G>A) is associated with xeroderma pigmentosum group E (ClinVar).

How common is DDB2 p.Thr246= (c.738G>A) in the general population?

DDB2 p.Thr246= (c.738G>A) is rare (popmax 0.86%, amr) (gnomAD).

How is Xeroderma pigmentosum inherited?

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

DDB2 p.Thr246=

c.738G>A · rs144266685 · VCV304919

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.86%, amr)

Conditions

xeroderma pigmentosum group E

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.18	GERP -1.1, phastCons 0.28
Overall
CADD	10.78	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.86% Admixed American · 516/60,004 alleles

Filtering AF 0.799% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.774%

Overall 0.227% 3,660/1,614,160 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.25%	80
Admixed Americangrpmax	0.86%	116
Middle Eastern	0.379%	264
Remaining individualsnot grpmax-eligible	0.349%	287
European (non-Finnish)	0.208%	481
South Asian	0.0461%	2,169
African / African-American	0.032%	3,127
Finnishnot grpmax-eligible	0.0219%	4,574
East Asian	0.00223%	44,882

Ashkenazi Jewish 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: DDB2
Protein: p.Thr246=
Coding: c.738G>A
MANE Select: NM_000107
dbSNP: rs144266685
Type: single nucleotide variant
Location: chr11:47234792 (GRCh38)
Gene constraint: LOEUF 0.719 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 83.69 · 10 PDB
Residue 246: a β-strand

Full DDB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

xeroderma pigmentosum group E — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Xeroderma pigmentosum (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

DDB2 c.702+1G>T Pathogenic/Likely pathogenic ★★ same condition
DDB2 p.Arg273His Pathogenic/Likely pathogenic ★★ ⚠ same condition
DDB2 p.Glu178Ala Uncertain significance ★★ ⚠ same condition
DDB2 p.Phe94Cys Uncertain significance ★★ ⚠ same condition
DDB2 p.Pro357Leu Uncertain significance ★★ ⚠ same condition
DDB2 p.Ser85Cys Uncertain significance ★★ ⚠ same condition
DDB2 p.Val263Ile Uncertain significance ★★ ⚠ same condition
DDB2 c.1189-21T>C Benign ★★ 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/ddb2-p-thr246 (accessed [today's date]).

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