Is DDB2 p.Val374Met (c.1120G>A) pathogenic?

DDB2 p.Val374Met (c.1120G>A) is classified Uncertain significance in DDB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-27). AlphaMissense: likely benign (0.1571); Ultra-rare (popmax 0.0986%, afr); Associated with xeroderma pigmentosum.

What condition is associated with DDB2 p.Val374Met (c.1120G>A)?

DDB2 p.Val374Met (c.1120G>A) is associated with xeroderma pigmentosum (ClinVar).

How common is DDB2 p.Val374Met (c.1120G>A) in the general population?

DDB2 p.Val374Met (c.1120G>A) is ultra-rare (popmax 0.0986%, afr) (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.Val374Met (c.1120G>A)?

AlphaMissense predicts likely benign (score 0.1571) — an in-silico prediction, not a clinical call.

DDB2 p.Val374Met

c.1120G>A · rs148299549 · VCV1692143

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1571 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0986%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

xeroderma pigmentosum

Computational evidence

Protein change
AlphaMissense	0.1571	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -9.69	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 0.55	GERP -1.1, phastCons 0.88
Regional constraint	o/e 0.78	unconstrained · MANE · 24 kb · p 1.9e-07 · regional, not allelic
Overall
CADD	16.76	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 0.0986% African / African-American · 74/75,032 alleles

Filtering AF 0.0805% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0739%

Overall 0.00675% 109/1,614,130 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0986%	1,014
Remaining individualsnot grpmax-eligible	0.0288%	3,473
Middle Eastern	0.0165%	6,062
Admixed American	0.00833%	11,999
South Asian	0.0022%	45,540
European (non-Finnish)	0.000763%	131,113

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.Val374Met
Coding: c.1120G>A
MANE Select: NM_000107
dbSNP: rs148299549
Type: single nucleotide variant
Location: chr11:47237933 (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 374: a β-strand

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

Disease context

xeroderma pigmentosum — 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 p.Cys66Gly Uncertain significance ★★ ⚠ same condition
DDB2 p.Met215Thr Likely benign ★★ same condition
DDB2 p.Pro290= Likely benign ★★ same condition
DDB2 c.127+5T>G Conflicting classifications of pathogenicity ★ same condition
DDB2 c.264+8A>G Conflicting classifications of pathogenicity ★ same condition
DDB2 c.603-4C>G Uncertain significance ★ same condition
DDB2 c.702+5G>A Uncertain significance ★ same condition
DDB2 p.Ala410Thr Conflicting classifications of pathogenicity ★ ⚠ 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-val374met (accessed [today's date]).

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