Is DDB2 p.Pro357Leu (c.1070C>T) pathogenic?

DDB2 p.Pro357Leu (c.1070C>T) is classified Uncertain significance in DDB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-04). AlphaMissense: likely pathogenic (0.7789); Very rare (popmax 0.00161%, nfe); Associated with xeroderma pigmentosum group E.

What condition is associated with DDB2 p.Pro357Leu (c.1070C>T)?

DDB2 p.Pro357Leu (c.1070C>T) is associated with xeroderma pigmentosum group E (ClinVar).

How common is DDB2 p.Pro357Leu (c.1070C>T) in the general population?

DDB2 p.Pro357Leu (c.1070C>T) is very rare (popmax 0.00161%, nfe) (gnomAD).

How is Xeroderma pigmentosum inherited?

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

What do computational predictors say about DDB2 p.Pro357Leu (c.1070C>T)?

AlphaMissense predicts likely pathogenic (score 0.7789) — an in-silico prediction, not a clinical call.

DDB2 p.Pro357Leu

c.1070C>T · rs780665825 · VCV304927

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7789 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

xeroderma pigmentosum group E

Computational evidence

Protein change
AlphaMissense	0.7789	likely pathogenic
REVEL	0.546	indeterminate
SaProt	LLR -9.91	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 24 kb · p 1.9e-07 · regional, not allelic
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00161% European (non-Finnish) · 19/1,180,034 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.0013% 21/1,614,048 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00161%	62,107
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00133%	74,914

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.Pro357Leu
Coding: c.1070C>T
MANE Select: NM_000107
dbSNP: rs780665825
Type: single nucleotide variant
Location: chr11:47237883 (GRCh38)
Gene constraint: LOEUF 0.719 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 83.69 · 10 PDB

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.Ser85Cys Uncertain significance ★★ ⚠ same condition
DDB2 p.Val263Ile Uncertain significance ★★ ⚠ same condition
DDB2 c.1189-21T>C Benign ★★ same condition
DDB2 c.1235-32A>G 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-pro357leu (accessed [today's date]).

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