Is CEP290 p.Arg1978Pro (c.5933G>C) pathogenic?

CEP290 p.Arg1978Pro (c.5933G>C) is classified Uncertain significance in CEP290 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-29). AlphaMissense: ambiguous (0.3861); Very rare (popmax 0.00221%, sas); Associated with Joubert syndrome 5.

What condition is associated with CEP290 p.Arg1978Pro (c.5933G>C)?

CEP290 p.Arg1978Pro (c.5933G>C) is associated with Joubert syndrome 5, Senior-Loken syndrome 6, Meckel syndrome, type 4 (ClinVar).

How common is CEP290 p.Arg1978Pro (c.5933G>C) in the general population?

CEP290 p.Arg1978Pro (c.5933G>C) is very rare (popmax 0.00221%, sas) (gnomAD).

What do computational predictors say about CEP290 p.Arg1978Pro (c.5933G>C)?

AlphaMissense predicts ambiguous (score 0.3861) — an in-silico prediction, not a clinical call.

CEP290 p.Arg1978Pro

c.5933G>C · VCV3575380

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3861 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00221%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Joubert syndrome 5

Computational evidence

Protein change
AlphaMissense	0.3861	ambiguous
REVEL	0.249	benign-leaning
SaProt	LLR -6.28	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.64, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 92 kb · p 0.89 · regional, not allelic
Overall
CADD	23.8	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 0.00221% South Asian · 2/90,688 alleles

Filtering AF 0.000366% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000124% 2/1,610,920 alleles · very rare exomes 2/1,458,722 · genomes 0/152,198 · joint denominator

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.Arg1978Pro
Coding: c.5933G>C
MANE Select: NM_025114
Type: single nucleotide variant
Location: chr12:88071372 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 60.90
Residue 1978: 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); a UniProt-annotated variant site (in mks4 and jbts5); the 'self-association (with itself or n-terminus)' region

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

Disease context

Joubert syndrome 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Senior-Loken syndrome 6 Meckel syndrome, type 4 Leber congenital amaurosis 10 Bardet-Biedl syndrome 14

Similar variants

CEP290 p.Arg1978Ter Pathogenic ★★ same residue
CEP290 p.Arg1978Gly Uncertain significance ★★ ⚠ same residue
CEP290 p.Arg1978Gln 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

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-arg1978pro (accessed [today's date]).

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