Is CEP104 p.Pro345Ala (c.1033C>G) pathogenic?

CEP104 p.Pro345Ala (c.1033C>G) is classified Uncertain significance in CEP104 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-02). AlphaMissense: likely benign (0.0644); Very rare (popmax 0.00445%, eas); Associated with Joubert syndrome 25.

What condition is associated with CEP104 p.Pro345Ala (c.1033C>G)?

CEP104 p.Pro345Ala (c.1033C>G) is associated with Joubert syndrome 25 (ClinVar).

How common is CEP104 p.Pro345Ala (c.1033C>G) in the general population?

CEP104 p.Pro345Ala (c.1033C>G) is very rare (popmax 0.00445%, eas) (gnomAD).

What do computational predictors say about CEP104 p.Pro345Ala (c.1033C>G)?

AlphaMissense predicts likely benign (score 0.0644) — an in-silico prediction, not a clinical call.

CEP104 p.Pro345Ala

c.1033C>G · rs745563257 · VCV2165788

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0644 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome 25

Computational evidence

Protein change
AlphaMissense	0.0644	likely benign
REVEL	0.099	moderately benign-leaning
SaProt	LLR -6.91	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 1.6	GERP -3, phastCons 0.98
Regional constraint	o/e 0.91	unconstrained · MANE · 37 kb · p 0.0023 · regional, not allelic
Overall
CADD	16.71	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 0.00445% East Asian · 2/44,904 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000372% 6/1,613,988 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,452
South Asian	0.0022%	45,541
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)	8.47e-05%	1,179,980

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: CEP104
Protein: p.Pro345Ala
Coding: c.1033C>G
MANE Select: NM_014704
dbSNP: rs745563257
Type: single nucleotide variant
Location: chr1:3837378 (GRCh38)
Gene constraint: LOEUF 0.851 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.75 · 2 PDB
Residue 345: a UniProt-annotated variant site (in mrt77)

Full CEP104 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Joubert syndrome 25 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CEP104 p.Arg299Ter Pathogenic/Likely pathogenic ★★ same condition
CEP104 p.Arg55Ter Pathogenic/Likely pathogenic ★★ same condition
CEP104 p.Glu627Ter Pathogenic/Likely pathogenic ★★ same condition
CEP104 p.Lys270Ter Pathogenic/Likely pathogenic ★★ same condition
CEP104 p.Tyr253Ter Pathogenic/Likely pathogenic ★★ same condition
CEP104 c.1120-5T>A Uncertain significance ★★ same condition
CEP104 p.Ala269Thr Uncertain significance ★★ ⚠ same condition
CEP104 p.Ala28Val Uncertain significance ★★ ⚠ 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/cep104-p-pro345ala (accessed [today's date]).

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