Is CPLANE1 p.Tyr2188Cys (c.6563A>G) pathogenic?

CPLANE1 p.Tyr2188Cys (c.6563A>G) is classified Uncertain significance in CPLANE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-12). AlphaMissense: likely benign (0.0674); Very rare (popmax 0.00266%, afr); Associated with orofaciodigital syndrome type 6.

What condition is associated with CPLANE1 p.Tyr2188Cys (c.6563A>G)?

CPLANE1 p.Tyr2188Cys (c.6563A>G) is associated with orofaciodigital syndrome type 6, Joubert syndrome 17 (ClinVar).

How common is CPLANE1 p.Tyr2188Cys (c.6563A>G) in the general population?

CPLANE1 p.Tyr2188Cys (c.6563A>G) is very rare (popmax 0.00266%, afr) (gnomAD).

What do computational predictors say about CPLANE1 p.Tyr2188Cys (c.6563A>G)?

AlphaMissense predicts likely benign (score 0.0674) — an in-silico prediction, not a clinical call.

CPLANE1 p.Tyr2188Cys

c.6563A>G · rs540226094 · VCV2062144

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0674 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00266%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

orofaciodigital syndrome type 6

Computational evidence

Protein change
AlphaMissense	0.0674	likely benign
REVEL	0.015	strongly 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 3.2	GERP -1.4, phastCons 0.4
Regional constraint	o/e 0.92	unconstrained · MANE · 139 kb · p 2.3e-06 · regional, not allelic
Overall
CADD	14.25	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 0.00266% African / African-American · 2/75,058 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000137% 2/1,461,872 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.Tyr2188Cys
Coding: c.6563A>G
MANE Select: NM_001384732
dbSNP: rs540226094
Type: single nucleotide variant
Location: chr5:37169461 (GRCh38)
Gene constraint: LOEUF 0.728 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2188: the 'disordered' region; 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

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

Also linked: Joubert syndrome 17

Similar variants

CPLANE1 p.Tyr2188Ter 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
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-tyr2188cys (accessed [today's date]).

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