Is CEP290 p.Ala1685= (c.5055G>A) pathogenic?

CEP290 p.Ala1685= (c.5055G>A) is classified Conflicting classifications of pathogenicity in CEP290 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.0315%, nfe); Associated with Leber congenital amaurosis 10.

What condition is associated with CEP290 p.Ala1685= (c.5055G>A)?

CEP290 p.Ala1685= (c.5055G>A) is associated with Leber congenital amaurosis 10, Joubert syndrome 5, Senior-Loken syndrome 6 (ClinVar).

How common is CEP290 p.Ala1685= (c.5055G>A) in the general population?

CEP290 p.Ala1685= (c.5055G>A) is ultra-rare (popmax 0.0315%, nfe) (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.Ala1685=

c.5055G>A · rs73192874 · VCV166834

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0315%, nfe)

Conditions

Leber congenital amaurosis 10

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 2.4	GERP -1.2, phastCons 1
Overall
CADD	10.22	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0315% European (non-Finnish) · 372/1,179,582 alleles

Filtering AF 0.0288% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0278%

Overall 0.0247% 398/1,613,246 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0315%	3,171
East Asian	0.0178%	5,604
African / African-American	0.0133%	7,498
Remaining individualsnot grpmax-eligible	0.00961%	10,410
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,590
South Asian	0.0011%	90,880

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.Ala1685=
Coding: c.5055G>A
MANE Select: NM_025114
dbSNP: rs73192874
Type: single nucleotide variant
Location: chr12:88080353 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.90
Residue 1685: a UniProt-annotated variant site (in lca10; also found in a patient with night blindness and hearing loss); a UniProt-annotated variant site (in lca10); a UniProt-annotated variant site (in lca10, slsn6 and mks4); a UniProt-annotated variant site (in lca10 and slsn6)

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

Disease context

Leber congenital amaurosis 10 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Joubert syndrome 5 Senior-Loken syndrome 6 Meckel syndrome, type 4 Bardet-Biedl syndrome 14 Joubert syndrome Meckel syndrome nephronophthisis inherited retinal dystrophy

For Leber congenital amaurosis (Orphanet):

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

Similar variants

CEP290 p.Ala1685Thr Uncertain significance ⚠ same residue
CEP290 c.1189+1G>A Pathogenic ★★★ same condition
CEP290 c.1189+2T>C Pathogenic ★★★ same condition
CEP290 c.297+1G>T Pathogenic ★★★ same condition
CEP290 c.2991+1655A>G Pathogenic ★★★ same condition
CEP290 c.6271-8T>G Pathogenic ★★★ same condition
CEP290 p.Arg1272Ter Pathogenic ★★★ same condition
CEP290 p.Arg1465Ter 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-ala1685 (accessed [today's date]).

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