Is CPLANE1 p.Ala1269Pro (c.3805G>C) pathogenic?

CPLANE1 p.Ala1269Pro (c.3805G>C) is classified Conflicting classifications of pathogenicity in CPLANE1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-01). AlphaMissense: likely pathogenic (0.7612); Very rare (popmax 0.000255%, nfe); Associated with Joubert syndrome and related disorders.

What condition is associated with CPLANE1 p.Ala1269Pro (c.3805G>C)?

CPLANE1 p.Ala1269Pro (c.3805G>C) is associated with Joubert syndrome and related disorders (ClinVar).

How common is CPLANE1 p.Ala1269Pro (c.3805G>C) in the general population?

CPLANE1 p.Ala1269Pro (c.3805G>C) is very rare (popmax 0.000255%, nfe) (gnomAD).

What do computational predictors say about CPLANE1 p.Ala1269Pro (c.3805G>C)?

AlphaMissense predicts likely pathogenic (score 0.7612) — an in-silico prediction, not a clinical call.

CPLANE1 p.Ala1269Pro

c.3805G>C · rs775914551 · VCV848883

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7612 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

Joubert syndrome and related disorders

Computational evidence

Protein change
AlphaMissense	0.7612	likely pathogenic · top 7% in CPLANE1
REVEL	0.19	benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 0.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 139 kb · p 2.3e-06 · regional, not allelic
Overall
CADD	24.2	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 0.000255% European (non-Finnish) · 3/1,178,478 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,608,996 alleles · very rare

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.Ala1269Pro
Coding: c.3805G>C
MANE Select: NM_001384732
dbSNP: rs775914551
Type: single nucleotide variant
Location: chr5:37195864 (GRCh38)
Gene constraint: LOEUF 0.728 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)

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

Disease context

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

Similar variants

CPLANE1 c.7400+1G>A Pathogenic ★★ same condition
CPLANE1 p.Ala1783Asp Pathogenic/Likely pathogenic ★★ same condition
CPLANE1 p.Arg1193Cys Pathogenic/Likely pathogenic ★★ same condition
CPLANE1 p.Arg1336Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
CPLANE1 p.Arg3074Ter Pathogenic/Likely pathogenic ★★ same condition
CPLANE1 p.Gln3033Ter Pathogenic ★★ same condition
CPLANE1 p.Glu142Lys Pathogenic/Likely pathogenic ★★ same condition
CPLANE1 p.Glu1464Ter 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-ala1269pro (accessed [today's date]).

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