Is CPLANE1 p.Pro375Ser (c.1123C>T) pathogenic?

CPLANE1 p.Pro375Ser (c.1123C>T) is classified Conflicting classifications of pathogenicity in CPLANE1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2024-04-02). AlphaMissense: likely benign (0.1555); Ultra-rare (popmax 0.0503%, mid); Associated with orofaciodigital syndrome type 6.

What condition is associated with CPLANE1 p.Pro375Ser (c.1123C>T)?

CPLANE1 p.Pro375Ser (c.1123C>T) is associated with orofaciodigital syndrome type 6, Joubert syndrome 17 (ClinVar).

How common is CPLANE1 p.Pro375Ser (c.1123C>T) in the general population?

CPLANE1 p.Pro375Ser (c.1123C>T) is ultra-rare (popmax 0.0503%, mid) (gnomAD).

What do computational predictors say about CPLANE1 p.Pro375Ser (c.1123C>T)?

AlphaMissense predicts likely benign (score 0.1555) — an in-silico prediction, not a clinical call.

CPLANE1 p.Pro375Ser

c.1123C>T · rs774016809 · VCV353462

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1555 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0503%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

orofaciodigital syndrome type 6

Computational evidence

Protein change
AlphaMissense	0.1555	likely benign
REVEL	0.159	moderately 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 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 139 kb · p 2.3e-06 · regional, not allelic
Overall
CADD	19.75	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 0.0503% Middle Eastern · 3/5,968 alleles

Filtering AF 0.0298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0261%

Overall 0.00885% 137/1,547,990 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.126%	793
Middle Easterngrpmax	0.0503%	1,989
South Asian	0.0406%	2,462
Remaining individualsnot grpmax-eligible	0.01%	9,996
Admixed American	0.00592%	16,879
European (non-Finnish)	0.0048%	20,823

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro375Ser
Coding: c.1123C>T
MANE Select: NM_001384732
dbSNP: rs774016809
Type: single nucleotide variant
Location: chr5:37227816 (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.Pro375= Benign/Likely benign ★★ same residue
CPLANE1 p.Pro375Leu 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

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-pro375ser (accessed [today's date]).

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