Is CPLANE1 p.Ile608Ser (c.1823T>G) pathogenic?

CPLANE1 p.Ile608Ser (c.1823T>G) is classified Uncertain significance in CPLANE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-12-16). AlphaMissense: ambiguous (0.4705); Ultra-rare (popmax 0.0122%, amr); Associated with orofaciodigital syndrome type 6.

What condition is associated with CPLANE1 p.Ile608Ser (c.1823T>G)?

CPLANE1 p.Ile608Ser (c.1823T>G) is associated with orofaciodigital syndrome type 6, Joubert syndrome 17 (ClinVar).

How common is CPLANE1 p.Ile608Ser (c.1823T>G) in the general population?

CPLANE1 p.Ile608Ser (c.1823T>G) is ultra-rare (popmax 0.0122%, amr) (gnomAD).

What do computational predictors say about CPLANE1 p.Ile608Ser (c.1823T>G)?

AlphaMissense predicts ambiguous (score 0.4705) — an in-silico prediction, not a clinical call.

CPLANE1 p.Ile608Ser

c.1823T>G · rs1194762831 · VCV1444464

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4705 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0122%, amr)

Conditions

orofaciodigital syndrome type 6

Computational evidence

Protein change
AlphaMissense	0.4705	ambiguous
REVEL	0.75	pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 139 kb · p 2.3e-06 · regional, not allelic
Overall
CADD	24.5	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 0.0122% Admixed American · 6/49,136 alleles

Filtering AF 0.00527% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00357%

Overall 0.000504% 7/1,390,102 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0122%	8,189
Remaining individualsnot grpmax-eligible	0.00167%	59,732

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.Ile608Ser
Coding: c.1823T>G
MANE Select: NM_001384732
dbSNP: rs1194762831
Type: single nucleotide variant
Location: chr5:37226772 (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.Ile608Val 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-ile608ser (accessed [today's date]).

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