Is CEP104 p.Ala28Val (c.83C>T) pathogenic?

CEP104 p.Ala28Val (c.83C>T) is classified Uncertain significance in CEP104 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-02-11). AlphaMissense: likely pathogenic (0.6352); Ultra-rare (popmax 0.011%, sas); Associated with Joubert syndrome 25.

What condition is associated with CEP104 p.Ala28Val (c.83C>T)?

CEP104 p.Ala28Val (c.83C>T) is associated with Joubert syndrome 25 (ClinVar).

How common is CEP104 p.Ala28Val (c.83C>T) in the general population?

CEP104 p.Ala28Val (c.83C>T) is ultra-rare (popmax 0.011%, sas) (gnomAD).

What do computational predictors say about CEP104 p.Ala28Val (c.83C>T)?

AlphaMissense predicts likely pathogenic (score 0.6352) — an in-silico prediction, not a clinical call.

CEP104 p.Ala28Val

c.83C>T · rs150169294 · VCV2045173

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6352 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Joubert syndrome 25

Computational evidence

Protein change
AlphaMissense	0.6352	likely pathogenic
REVEL	0.562	indeterminate
SaProt	LLR -10.91	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 37 kb · p 0.0023 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.011% South Asian · 10/91,086 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.00576% 93/1,613,936 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0192%	5,207
South Asiangrpmax	0.011%	9,109
Finnishnot grpmax-eligible	0.00626%	15,983
European (non-Finnish)	0.00534%	18,731
Admixed American	0.00333%	29,994
African / African-American	0.00267%	37,462

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala28Val
Coding: c.83C>T
MANE Select: NM_014704
dbSNP: rs150169294
Type: single nucleotide variant
Location: chr1:3852325 (GRCh38)
Gene constraint: LOEUF 0.851 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.75 · 2 PDB

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.Ala28= Likely benign ★ same residue
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

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-ala28val (accessed [today's date]).

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