Is CPLANE1 p.Pro2893Leu (c.8678C>T) pathogenic?

CPLANE1 p.Pro2893Leu (c.8678C>T) is classified Conflicting classifications of pathogenicity in CPLANE1 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.1236); Ultra-rare (popmax 0.0828%, mid); Associated with Inborn genetic diseases.

What condition is associated with CPLANE1 p.Pro2893Leu (c.8678C>T)?

CPLANE1 p.Pro2893Leu (c.8678C>T) is associated with Inborn genetic diseases, orofaciodigital syndrome type 6, Joubert syndrome 17 (ClinVar).

How common is CPLANE1 p.Pro2893Leu (c.8678C>T) in the general population?

CPLANE1 p.Pro2893Leu (c.8678C>T) is ultra-rare (popmax 0.0828%, mid) (gnomAD).

What do computational predictors say about CPLANE1 p.Pro2893Leu (c.8678C>T)?

AlphaMissense predicts likely benign (score 0.1236) — an in-silico prediction, not a clinical call.

CPLANE1 p.Pro2893Leu

c.8678C>T · rs147426388 · VCV353421

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1236 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0828%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1236	likely benign
REVEL	0.049	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.6	GERP -0.28, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 139 kb · p 2.3e-06 · regional, not allelic
Overall
CADD	20.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P2839L vs ClinVar P2893L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0828% Middle Eastern · 5/6,036 alleles

Filtering AF 0.0731% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0714%

Overall 0.0636% 1,023/1,607,304 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0828%	1,207
European (non-Finnish)	0.0772%	1,295
Admixed American	0.0533%	1,876
Remaining individualsnot grpmax-eligible	0.045%	2,225
Ashkenazi Jewishnot grpmax-eligible	0.0442%	2,260
Finnishnot grpmax-eligible	0.0219%	4,568
East Asian	0.0157%	6,382
African / African-American	0.0107%	9,343
South Asian	0.00786%	12,726

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: CPLANE1
Protein: p.Pro2893Leu
Coding: c.8678C>T
MANE Select: NM_001384732
dbSNP: rs147426388
Type: single nucleotide variant
Location: chr5:37138834 (GRCh38)
Gene constraint: LOEUF 0.728 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2893: a UniProt-annotated variant site (in ofd6; likely pathogenic)

Full CPLANE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: orofaciodigital syndrome type 6 Joubert syndrome 17

Similar variants

CPLANE1 p.Pro2893= Likely benign ★★ same residue
CPLANE1 c.1372-2A>G Pathogenic/Likely pathogenic ★★ same condition
CPLANE1 c.2291+1G>A Likely pathogenic ★★ same condition
CPLANE1 c.2291+2T>C Pathogenic/Likely pathogenic ★★ same condition
CPLANE1 c.2292-1G>A Likely pathogenic ★★ same condition
CPLANE1 c.2500+1G>A Likely pathogenic ★★ same condition
CPLANE1 c.3290-2A>G Pathogenic/Likely pathogenic ★★ same condition
CPLANE1 c.3673-1G>C Pathogenic/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/cplane1-p-pro2893leu (accessed [today's date]).

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