Is CPLANE1 p.Ser1127Leu (c.3380C>T) pathogenic?

CPLANE1 p.Ser1127Leu (c.3380C>T) is classified Pathogenic/Likely pathogenic in CPLANE1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-02-26). AlphaMissense: likely benign (0.179); Very rare (popmax 0.000339%, nfe); Associated with Joubert syndrome 17.

What condition is associated with CPLANE1 p.Ser1127Leu (c.3380C>T)?

CPLANE1 p.Ser1127Leu (c.3380C>T) is associated with Joubert syndrome 17, orofaciodigital syndrome type 6 (ClinVar).

How common is CPLANE1 p.Ser1127Leu (c.3380C>T) in the general population?

CPLANE1 p.Ser1127Leu (c.3380C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about CPLANE1 p.Ser1127Leu (c.3380C>T)?

AlphaMissense predicts likely benign (score 0.179) — an in-silico prediction, not a clinical call.

CPLANE1 p.Ser1127Leu

c.3380C>T · rs375009168 · VCV157515

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.179 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

Joubert syndrome 17

Computational evidence

Protein change
AlphaMissense	0.179	likely benign ⚠ discordant with ClinVar
REVEL	0.668	pathogenic-leaning
⇒ REVEL calls this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 139 kb · p 2.3e-06 · regional, not allelic
Overall
CADD	28.3	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 0.000339% European (non-Finnish) · 4/1,179,954 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,772 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.Ser1127Leu
Coding: c.3380C>T
MANE Select: NM_001384732
dbSNP: rs375009168
Type: single nucleotide variant
Location: chr5:37201718 (GRCh38)
Gene constraint: LOEUF 0.728 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1127: a UniProt-annotated variant site (in ofd6)

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 p.Ser1127Ala Uncertain significance ★★ ⚠ same residue
CPLANE1 p.Ser1127= Likely benign ★★ same residue
CPLANE1 p.Ser1127Ter Pathogenic ★ 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

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-ser1127leu (accessed [today's date]).

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