Is CEP290 p.Asp321Val (c.962A>T) pathogenic?

CEP290 p.Asp321Val (c.962A>T) is classified Uncertain significance in CEP290 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-11). AlphaMissense: likely pathogenic (0.76); Very rare (popmax 0.00139%, sas); Associated with Joubert syndrome.

What condition is associated with CEP290 p.Asp321Val (c.962A>T)?

CEP290 p.Asp321Val (c.962A>T) is associated with Joubert syndrome, Meckel syndrome, nephronophthisis (ClinVar).

How common is CEP290 p.Asp321Val (c.962A>T) in the general population?

CEP290 p.Asp321Val (c.962A>T) is very rare (popmax 0.00139%, sas) (gnomAD).

What do computational predictors say about CEP290 p.Asp321Val (c.962A>T)?

AlphaMissense predicts likely pathogenic (score 0.76) — an in-silico prediction, not a clinical call.

CEP290 p.Asp321Val

c.962A>T · rs759074453 · VCV1948095

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.76 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00139%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Joubert syndrome

Computational evidence

Protein change
AlphaMissense	0.76	likely pathogenic · top 6% in CEP290
REVEL	0.516	indeterminate
SaProt	LLR -9.32	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.69 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 2.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 92 kb · p 0.89 · regional, not allelic
Overall
CADD	29.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00139% South Asian · 1/71,714 alleles

Overall 7.39e-05% 1/1,353,808 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.Asp321Val
Coding: c.962A>T
MANE Select: NM_025114
dbSNP: rs759074453
Type: single nucleotide variant
Location: chr12:88126419 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.90
Residue 321: 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

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

Also linked: Meckel syndrome nephronophthisis

Similar variants

CEP290 p.Asp321Glu Uncertain significance ★★★ ⚠ same residue
CEP290 p.Asp321Asn 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

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-asp321val (accessed [today's date]).

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