Is CEP290 p.Asp128fs (c.384_385del) pathogenic?

CEP290 p.Asp128fs (c.384385del) is classified Pathogenic/Likely pathogenic in CEP290 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-01-28). Very rare (popmax 0.0011%, sas); Associated with Leber congenital amaurosis.

What condition is associated with CEP290 p.Asp128fs (c.384_385del)?

CEP290 p.Asp128fs (c.384_385del) is associated with Leber congenital amaurosis, Bardet-Biedl syndrome 14, Joubert syndrome (ClinVar).

How common is CEP290 p.Asp128fs (c.384_385del) in the general population?

CEP290 p.Asp128fs (c.384_385del) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Leber congenital amaurosis inherited?

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

CEP290 p.Asp128fs

c.384_385del · rs1288619268 · VCV1098750

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Leber congenital amaurosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 54
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.2	GERP 1.4, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,056 alleles

Overall 0.000137% 2/1,461,110 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,056
European (non-Finnish)	8.48e-05%	1,179,394

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: CEP290
Protein: p.Asp128fs
Coding: c.384_385del
MANE Select: NM_025114
dbSNP: rs1288619268
Type: Deletion
Location: chr12:88136699 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.90
Residue 128: the 'self-association (with itself or c-terminus)' region; a UniProt-annotated variant site (in lca10; also found in a patient with night blindness and hearing loss)

Full CEP290 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Leber congenital amaurosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Bardet-Biedl syndrome 14 Joubert syndrome Meckel syndrome nephronophthisis

For Leber congenital amaurosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CEP290 p.Asp128His Uncertain significance ★★ ⚠ same residue
CEP290 p.Asp128= Conflicting classifications of pathogenicity ★ same residue
CEP290 p.Asp128Tyr Uncertain significance ★ ⚠ same residue
CEP290 p.Asp128Val Uncertain significance ★ ⚠ same residue
CEP290 c.4438-3del Pathogenic ★★★ same condition
CEP290 p.Asn737_Leu738insTer Pathogenic ★★★ same condition
CEP290 p.Ile556fs Pathogenic ★★★ same condition
CEP290 p.Lys1343fs Pathogenic ★★★ 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/cep290-p-asp128fs (accessed [today's date]).

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