Is CPLANE1 p.Arg216Trp (c.646C>T) pathogenic?

CPLANE1 p.Arg216Trp (c.646C>T) is classified Uncertain significance in CPLANE1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-08-09). AlphaMissense: likely benign (0.1169); Very rare (popmax 0.00246%, eas); Associated with orofaciodigital syndrome type 6.

What condition is associated with CPLANE1 p.Arg216Trp (c.646C>T)?

CPLANE1 p.Arg216Trp (c.646C>T) is associated with orofaciodigital syndrome type 6, Joubert syndrome 17 (ClinVar).

How common is CPLANE1 p.Arg216Trp (c.646C>T) in the general population?

CPLANE1 p.Arg216Trp (c.646C>T) is very rare (popmax 0.00246%, eas) (gnomAD).

What do computational predictors say about CPLANE1 p.Arg216Trp (c.646C>T)?

AlphaMissense predicts likely benign (score 0.1169) — an in-silico prediction, not a clinical call.

CPLANE1 p.Arg216Trp

c.646C>T · rs543556323 · VCV1312026

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1169 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

orofaciodigital syndrome type 6

Computational evidence

Protein change
AlphaMissense	0.1169	likely benign
REVEL	0.131	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	Δ0.20	donor loss, 31 bp away · masked 0 · deltas
Pangolin	Δ0.24	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6.2	GERP -0.094, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 139 kb · p 2.3e-06 · regional, not allelic
Overall
CADD	26.4	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 0.00246% East Asian · 1/40,584 alleles

Filtering AF 0.00142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00119%

Overall 0.00188% 29/1,545,994 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00246%	40,584
South Asian	0.00241%	41,571
European (non-Finnish)	0.0021%	47,682
Remaining individualsnot grpmax-eligible	0.00167%	59,896
African / African-American	0.00137%	72,758

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.Arg216Trp
Coding: c.646C>T
MANE Select: NM_001384732
dbSNP: rs543556323
Type: single nucleotide variant
Location: chr5:37243044 (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

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

Also linked: Joubert syndrome 17

Similar variants

CPLANE1 p.Arg216Gln Uncertain significance ★ ⚠ 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-arg216trp (accessed [today's date]).

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