Is CEP63 p.Ala456= (c.1368A>G) pathogenic?

CEP63 p.Ala456= (c.1368A>G) is classified Conflicting classifications of pathogenicity in CEP63 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-06-09). Ultra-rare (popmax 0.0822%, mid); Associated with Seckel syndrome 6.

What condition is associated with CEP63 p.Ala456= (c.1368A>G)?

CEP63 p.Ala456= (c.1368A>G) is associated with Seckel syndrome 6 (ClinVar).

How common is CEP63 p.Ala456= (c.1368A>G) in the general population?

CEP63 p.Ala456= (c.1368A>G) is ultra-rare (popmax 0.0822%, mid) (gnomAD).

CEP63 p.Ala456=

c.1368A>G · rs372685774 · VCV1593774

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0822%, mid)

Conditions

Seckel syndrome 6

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.069	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.91	GERP -0.8
Overall
CADD	9.453	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0822% Middle Eastern · 5/6,084 alleles

Filtering AF 0.0323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.00985% 159/1,614,072 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0822%	1,217
South Asian	0.0143%	7,007
European (non-Finnish)	0.0109%	9,147
Admixed American	0.00833%	12,001
Remaining individualsnot grpmax-eligible	0.008%	12,497
African / African-American	0.00267%	37,476

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: CEP63
Protein: p.Ala456=
Coding: c.1368A>G
MANE Select: NM_001353108
dbSNP: rs372685774
Type: single nucleotide variant
Location: chr3:134550248 (GRCh38)
Gene constraint: LOEUF 1.127 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.95 · 4 PDB
Residue 456: an α-helix

Full CEP63 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Seckel syndrome 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CEP63 c.1067+2T>C Likely pathogenic ★★ same condition
CEP63 c.790-2A>G Likely pathogenic ★★ same condition
CEP63 p.Arg312Gln Uncertain significance ★★ ⚠ same condition
CEP63 p.Asn223Ser Uncertain significance ★★ ⚠ same condition
CEP63 p.Lys553Glu Uncertain significance ★★ ⚠ same condition
CEP63 p.Pro658His Uncertain significance ★★ ⚠ same condition
CEP63 c.1330-16A>G Benign/Likely benign ★★ same condition
CEP63 c.790-1G>A Likely 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/cep63-p-ala456 (accessed [today's date]).

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