Is CEP104 p.Arg656Cys (c.1966C>T) pathogenic?

CEP104 p.Arg656Cys (c.1966C>T) is classified Benign/Likely benign in CEP104 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.2247); Rare (popmax 0.508%, nfe); Associated with Joubert syndrome 25.

What condition is associated with CEP104 p.Arg656Cys (c.1966C>T)?

CEP104 p.Arg656Cys (c.1966C>T) is associated with Joubert syndrome 25 (ClinVar).

How common is CEP104 p.Arg656Cys (c.1966C>T) in the general population?

CEP104 p.Arg656Cys (c.1966C>T) is rare (popmax 0.508%, nfe) (gnomAD).

What do computational predictors say about CEP104 p.Arg656Cys (c.1966C>T)?

AlphaMissense predicts likely benign (score 0.2247) — an in-silico prediction, not a clinical call.

CEP104 p.Arg656Cys

c.1966C>T · rs148465057 · VCV707355

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.2247 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.508%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Joubert syndrome 25

Computational evidence

Protein change
AlphaMissense	0.2247	likely benign
REVEL	0.409	indeterminate
SaProt	LLR -13.28	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 37 kb · p 0.0023 · regional, not allelic
Overall
CADD	32.0	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 0.508% European (non-Finnish) · 5,989/1,180,008 alleles

Filtering AF 0.497% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.492%

Overall 0.408% 6,579/1,614,086 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.508%	197
Remaining individualsnot grpmax-eligible	0.336%	298
Middle Eastern	0.148%	674
South Asian	0.148%	675
Finnishnot grpmax-eligible	0.119%	842
Amishnot grpmax-eligible	0.11%	912
Admixed American	0.105%	953
African / African-American	0.0933%	1,072
East Asian	0.0379%	2,640
Ashkenazi Jewishnot grpmax-eligible	0.0304%	3,289

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.Arg656Cys
Coding: c.1966C>T
MANE Select: NM_014704
dbSNP: rs148465057
Type: single nucleotide variant
Location: chr1:3829868 (GRCh38)
Gene constraint: LOEUF 0.851 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.75 · 2 PDB
Residue 656: a UniProt-annotated variant site (in mrt77); an α-helix

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-arg656cys (accessed [today's date]).

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