Is CPLANE1 p.Arg1044Cys (c.3130C>T) pathogenic?

CPLANE1 p.Arg1044Cys (c.3130C>T) is classified Uncertain significance in CPLANE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-13). AlphaMissense: likely benign (0.0824); Ultra-rare (popmax 0.0196%, amr); Associated with orofaciodigital syndrome type 6.

What condition is associated with CPLANE1 p.Arg1044Cys (c.3130C>T)?

CPLANE1 p.Arg1044Cys (c.3130C>T) is associated with orofaciodigital syndrome type 6, Joubert syndrome 17 (ClinVar).

How common is CPLANE1 p.Arg1044Cys (c.3130C>T) in the general population?

CPLANE1 p.Arg1044Cys (c.3130C>T) is ultra-rare (popmax 0.0196%, amr) (gnomAD).

What do computational predictors say about CPLANE1 p.Arg1044Cys (c.3130C>T)?

AlphaMissense predicts likely benign (score 0.0824) — an in-silico prediction, not a clinical call.

CPLANE1 p.Arg1044Cys

c.3130C>T · rs376987361 · VCV1361643

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0824 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0196%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

orofaciodigital syndrome type 6

Computational evidence

Protein change
AlphaMissense	0.0824	likely benign
REVEL	0.033	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.57 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.78	GERP 0.89
Regional constraint	o/e 0.92	unconstrained · MANE · 139 kb · p 2.3e-06 · regional, not allelic
Overall
CADD	21.9	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 0.0196% Admixed American · 10/50,972 alleles

Filtering AF 0.0106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00809%

Overall 0.00593% 92/1,551,226 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0196%	5,097
Middle Eastern	0.0166%	6,012
African / African-American	0.0123%	8,113
Remaining individualsnot grpmax-eligible	0.00831%	12,028
European (non-Finnish)	0.00567%	17,640
East Asian	0.00244%	40,932
South Asian	0.00119%	84,046

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.Arg1044Cys
Coding: c.3130C>T
MANE Select: NM_001384732
dbSNP: rs376987361
Type: single nucleotide variant
Location: chr5:37206216 (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.Arg1044fs Pathogenic ★★ same residue
CPLANE1 p.Arg1044His Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg1044cys (accessed [today's date]).

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