Is CPLANE1 p.Ser2916Pro (c.8746T>C) pathogenic?

CPLANE1 p.Ser2916Pro (c.8746T>C) is classified Uncertain significance in CPLANE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-24). AlphaMissense: ambiguous (0.3422); Ultra-rare (popmax 0.0291%, eas); Associated with orofaciodigital syndrome type 6.

What condition is associated with CPLANE1 p.Ser2916Pro (c.8746T>C)?

CPLANE1 p.Ser2916Pro (c.8746T>C) is associated with orofaciodigital syndrome type 6, Joubert syndrome 17 (ClinVar).

How common is CPLANE1 p.Ser2916Pro (c.8746T>C) in the general population?

CPLANE1 p.Ser2916Pro (c.8746T>C) is ultra-rare (popmax 0.0291%, eas) (gnomAD).

What do computational predictors say about CPLANE1 p.Ser2916Pro (c.8746T>C)?

AlphaMissense predicts ambiguous (score 0.3422) — an in-silico prediction, not a clinical call.

CPLANE1 p.Ser2916Pro

c.8746T>C · rs139554617 · VCV1058234

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3422 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0291%, eas)

Conditions

orofaciodigital syndrome type 6

Computational evidence

Protein change
AlphaMissense	0.3422	ambiguous
REVEL	0.312	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 139 kb · p 2.3e-06 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S2862P vs ClinVar S2916P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0291% East Asian · 13/44,750 alleles

Filtering AF 0.0171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00124% 20/1,613,170 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0291%	3,442
Remaining individualsnot grpmax-eligible	0.0016%	62,464
European (non-Finnish)	0.000509%	196,593

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.Ser2916Pro
Coding: c.8746T>C
MANE Select: NM_001384732
dbSNP: rs139554617
Type: single nucleotide variant
Location: chr5:37138766 (GRCh38)
Gene constraint: LOEUF 0.728 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 2916: 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.Ser2916Cys 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-ser2916pro (accessed [today's date]).

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