Is CPLANE1 p.Pro2272Leu (c.6815C>T) pathogenic?

CPLANE1 p.Pro2272Leu (c.6815C>T) is classified Uncertain significance in CPLANE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-23). AlphaMissense: likely benign (0.0928); Very rare (popmax 0.000424%, nfe); Associated with Joubert syndrome 17.

What condition is associated with CPLANE1 p.Pro2272Leu (c.6815C>T)?

CPLANE1 p.Pro2272Leu (c.6815C>T) is associated with Joubert syndrome 17, orofaciodigital syndrome type 6 (ClinVar).

How common is CPLANE1 p.Pro2272Leu (c.6815C>T) in the general population?

CPLANE1 p.Pro2272Leu (c.6815C>T) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about CPLANE1 p.Pro2272Leu (c.6815C>T)?

AlphaMissense predicts likely benign (score 0.0928) — an in-silico prediction, not a clinical call.

CPLANE1 p.Pro2272Leu

c.6815C>T · rs777757781 · VCV940125

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0928 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Joubert syndrome 17

Computational evidence

Protein change
AlphaMissense	0.0928	likely benign
REVEL	0.045	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 0.67	GERP 0.74, phastCons 0.002
Regional constraint	o/e 0.92	unconstrained · MANE · 139 kb · p 2.3e-06 · regional, not allelic
Overall
CADD	11.14	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000424% European (non-Finnish) · 5/1,180,010 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00041% 6/1,461,826 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)grpmax	0.000424%	236,002

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: CPLANE1
Protein: p.Pro2272Leu
Coding: c.6815C>T
MANE Select: NM_001384732
dbSNP: rs777757781
Type: single nucleotide variant
Location: chr5:37169209 (GRCh38)
Gene constraint: LOEUF 0.728 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2272: 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

Joubert syndrome 17 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: orofaciodigital syndrome type 6

Similar variants

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
CPLANE1 c.677+1G>C 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-pro2272leu (accessed [today's date]).

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