Is CEP290 p.Ala63Val (c.188C>T) pathogenic?

CEP290 p.Ala63Val (c.188C>T) is classified Uncertain significance in CEP290 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-15). AlphaMissense: likely benign (0.1483); Ultra-rare (popmax 0.0133%, sas); Associated with Joubert syndrome.

What condition is associated with CEP290 p.Ala63Val (c.188C>T)?

CEP290 p.Ala63Val (c.188C>T) is associated with Joubert syndrome, Meckel syndrome, Leber congenital amaurosis (ClinVar).

How common is CEP290 p.Ala63Val (c.188C>T) in the general population?

CEP290 p.Ala63Val (c.188C>T) is ultra-rare (popmax 0.0133%, sas) (gnomAD).

What do computational predictors say about CEP290 p.Ala63Val (c.188C>T)?

AlphaMissense predicts likely benign (score 0.1483) — an in-silico prediction, not a clinical call.

CEP290 p.Ala63Val

c.188C>T · rs769705891 · VCV1020815

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1483 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.1483	likely benign
REVEL	0.15	moderately benign-leaning
SaProt	LLR -6.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 92 kb · p 0.89 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% South Asian · 11/82,792 alleles

Filtering AF 0.00741% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00569%

Overall 0.000826% 13/1,573,850 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0133%	7,527
Remaining individualsnot grpmax-eligible	0.00165%	60,452
European (non-Finnish)	8.61e-05%	1,161,478

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.Ala63Val
Coding: c.188C>T
MANE Select: NM_025114
dbSNP: rs769705891
Type: single nucleotide variant
Location: chr12:88139557 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.90
Residue 63: 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

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

Also linked: Meckel syndrome Leber congenital amaurosis nephronophthisis

Similar variants

CEP290 p.Ala63= Likely benign ★★ 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-ala63val (accessed [today's date]).

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