Is CEP104 p.Met321Val (c.961A>G) pathogenic?

CEP104 p.Met321Val (c.961A>G) is classified Conflicting classifications of pathogenicity in CEP104 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-24). AlphaMissense: likely benign (0.0512); Ultra-rare (popmax 0.025%, amr); Associated with Joubert syndrome 25.

What condition is associated with CEP104 p.Met321Val (c.961A>G)?

CEP104 p.Met321Val (c.961A>G) is associated with Joubert syndrome 25 (ClinVar).

How common is CEP104 p.Met321Val (c.961A>G) in the general population?

CEP104 p.Met321Val (c.961A>G) is ultra-rare (popmax 0.025%, amr) (gnomAD).

What do computational predictors say about CEP104 p.Met321Val (c.961A>G)?

AlphaMissense predicts likely benign (score 0.0512) — an in-silico prediction, not a clinical call.

CEP104 p.Met321Val

c.961A>G · rs144278349 · VCV2037282

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0512 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.025%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Joubert syndrome 25

Computational evidence

Protein change
AlphaMissense	0.0512	likely benign
REVEL	0.012	strongly benign-leaning
SaProt	LLR -5.12	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 -4.1	GERP -3.5
Regional constraint	o/e 0.91	unconstrained · MANE · 37 kb · p 0.0023 · regional, not allelic
Overall
CADD	0.005	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 0.025% Admixed American · 15/59,996 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.00235% 38/1,614,106 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.025%	4,000
African / African-American	0.004%	24,977
Remaining individualsnot grpmax-eligible	0.0032%	31,241
European (non-Finnish)	0.00144%	69,415
South Asian	0.0011%	91,092

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.Met321Val
Coding: c.961A>G
MANE Select: NM_014704
dbSNP: rs144278349
Type: single nucleotide variant
Location: chr1:3837450 (GRCh38)
Gene constraint: LOEUF 0.851 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.75 · 2 PDB
Residue 321: 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.Met321Ile Uncertain significance ★★ ⚠ 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-met321val (accessed [today's date]).

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