Is CEP290 p.Met1Val (c.1A>G) pathogenic?

CEP290 p.Met1Val (c.1A>G) is classified Pathogenic/Likely pathogenic in CEP290 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-11-05). Very rare (popmax 0.00017%, nfe); Associated with Meckel syndrome.

What condition is associated with CEP290 p.Met1Val (c.1A>G)?

CEP290 p.Met1Val (c.1A>G) is associated with Meckel syndrome, Joubert syndrome, nephronophthisis (ClinVar).

How common is CEP290 p.Met1Val (c.1A>G) in the general population?

CEP290 p.Met1Val (c.1A>G) is very rare (popmax 0.00017%, nfe) (gnomAD).

CEP290 p.Met1Val

c.1A>G · rs2040644756 · VCV871410

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

Meckel syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.636	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.4, phastCons 1
Overall
CADD	24.6	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 0.00017% European (non-Finnish) · 2/1,173,726 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000138% 2/1,452,806 alleles · very rare

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.Met1Val
Coding: c.1A>G
MANE Select: NM_025114
dbSNP: rs2040644756
Type: single nucleotide variant
Location: chr12:88141307 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.90
Residue 1: the 'self-association (with itself or c-terminus)' region

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

Disease context

Meckel syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Joubert syndrome nephronophthisis inherited retinal dystrophy

Similar variants

CEP290 p.Met1Lys Pathogenic ★★★ same residue
CEP290 p.Met1Ile Pathogenic/Likely pathogenic ★★ same residue
CEP290 p.Met1fs Pathogenic ★ 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

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-met1val (accessed [today's date]).

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