Is DDB2 p.Phe94Cys (c.281T>G) pathogenic?

DDB2 p.Phe94Cys (c.281T>G) is classified Uncertain significance in DDB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-12). AlphaMissense: likely pathogenic (0.5941); Ultra-rare (popmax 0.0144%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DDB2 p.Phe94Cys (c.281T>G)?

DDB2 p.Phe94Cys (c.281T>G) is associated with Inborn genetic diseases, xeroderma pigmentosum group E (ClinVar).

How common is DDB2 p.Phe94Cys (c.281T>G) in the general population?

DDB2 p.Phe94Cys (c.281T>G) is ultra-rare (popmax 0.0144%, nfe) (gnomAD).

What do computational predictors say about DDB2 p.Phe94Cys (c.281T>G)?

AlphaMissense predicts likely pathogenic (score 0.5941) — an in-silico prediction, not a clinical call.

DDB2 p.Phe94Cys

c.281T>G · rs144729572 · VCV2369982

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5941 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0144%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5941	likely pathogenic
REVEL	0.614	indeterminate
SaProt	LLR -8.59	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 6.1	GERP 2.3, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 24 kb · p 1.9e-07 · regional, not allelic
Overall
CADD	27.9	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 0.0144% European (non-Finnish) · 170/1,180,016 alleles

Filtering AF 0.0126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.0108% 175/1,613,942 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0144%	6,941
Remaining individualsnot grpmax-eligible	0.008%	12,496

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.Phe94Cys
Coding: c.281T>G
MANE Select: NM_000107
dbSNP: rs144729572
Type: single nucleotide variant
Location: chr11:47216874 (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 94: the 'required for interaction with ddb1' region; a turn

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: xeroderma pigmentosum group E

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.Pro27Thr Uncertain significance ★★ ⚠ same condition
DDB2 p.Pro357Leu Uncertain significance ★★ ⚠ same condition
DDB2 p.Ser85Cys Uncertain significance ★★ ⚠ same condition
DDB2 p.Ser85Tyr Uncertain significance ★★ ⚠ same condition
DDB2 p.Thr406Met Uncertain significance ★★ ⚠ 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-phe94cys (accessed [today's date]).

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