Is CEP290 p.Arg1237fs (c.3708dup) pathogenic?

CEP290 p.Arg1237fs (c.3708dup) is classified Pathogenic/Likely pathogenic in CEP290 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-06-12). Very rare (popmax 0.0011%, sas); Associated with CEP290-related disorder.

What condition is associated with CEP290 p.Arg1237fs (c.3708dup)?

CEP290 p.Arg1237fs (c.3708dup) is associated with CEP290-related disorder, Joubert syndrome 5, Meckel syndrome, type 4 (ClinVar).

How common is CEP290 p.Arg1237fs (c.3708dup) in the general population?

CEP290 p.Arg1237fs (c.3708dup) is very rare (popmax 0.0011%, sas) (gnomAD).

CEP290 p.Arg1237fs

c.3708dup · rs758991387 · VCV1071036

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

CEP290-related disorder

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 31 of 54
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 9.9	phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,080 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000313%

Overall 0.000744% 12/1,613,742 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,460
South Asiangrpmax	0.0011%	91,080
European (non-Finnish)	0.000848%	117,988

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg1237fs
Coding: c.3708dup
MANE Select: NM_025114
dbSNP: rs758991387
Type: Duplication
Location: chr12:88089352 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.90
Residue 1237: 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)

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

Disease context

Also linked: Joubert syndrome 5 Meckel syndrome, type 4 Leber congenital amaurosis 10 Bardet-Biedl syndrome 14 Senior-Loken syndrome Joubert syndrome Meckel syndrome Leber congenital amaurosis nephronophthisis CEP290-related ciliopathy

Similar variants

CEP290 p.Arg1237Cys Uncertain significance ★★ ⚠ same residue
CEP290 p.Arg1237Leu Uncertain significance ★★ ⚠ same residue
CEP290 p.Arg1237His Benign/Likely benign ★★ same residue
CEP290 p.Asn1775fs Pathogenic ★★★ same condition
CEP290 p.Asn85fs Likely pathogenic ★★★ same condition
CEP290 p.Asp450fs Likely pathogenic ★★★ same condition
CEP290 p.Leu1155fs Likely pathogenic ★★★ same condition
CEP290 p.Lys1042Ter 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-arg1237fs (accessed [today's date]).

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