Is CPLANE1 p.Pro728Ala (c.2182C>G) pathogenic?

CPLANE1 p.Pro728Ala (c.2182C>G) is classified Uncertain significance in CPLANE1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-07-12). AlphaMissense: likely benign (0.2529); Very rare (popmax 0.00148%, nfe).

How common is CPLANE1 p.Pro728Ala (c.2182C>G) in the general population?

CPLANE1 p.Pro728Ala (c.2182C>G) is very rare (popmax 0.00148%, nfe) (gnomAD).

What do computational predictors say about CPLANE1 p.Pro728Ala (c.2182C>G)?

AlphaMissense predicts likely benign (score 0.2529) — an in-silico prediction, not a clinical call.

CPLANE1 p.Pro728Ala

c.2182C>G · rs1467926733 · VCV434553

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2529 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00148%, nfe)

Computational evidence

Protein change
AlphaMissense	0.2529	likely benign
REVEL	0.299	indeterminate
Splicing
SpliceAI	Δ0.60	acceptor loss, 12 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 8.6	GERP 0.54, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 139 kb · p 2.3e-06 · regional, not allelic
Overall
CADD	22.9	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 0.00148% European (non-Finnish) · 17/1,146,578 alleles

Filtering AF 0.000903% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000738%

Overall 0.0011% 17/1,550,168 alleles · very rare

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.Pro728Ala
Coding: c.2182C>G
MANE Select: NM_001384732
dbSNP: rs1467926733
Type: single nucleotide variant
Location: chr5:37226413 (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

Similar variants

CPLANE1 p.Pro728Leu Uncertain significance ★ same residue
CPLANE1 c.1372-2A>G Pathogenic/Likely pathogenic ★★ same type
CPLANE1 c.2291+1G>A Likely pathogenic ★★ same type
CPLANE1 c.2291+2T>C Pathogenic/Likely pathogenic ★★ same type
CPLANE1 c.2292-1G>A Likely pathogenic ★★ same type
CPLANE1 c.2500+1G>A Likely pathogenic ★★ same type
CPLANE1 c.2920+1G>A Likely pathogenic ★★ same type
CPLANE1 c.3290-2A>G Pathogenic/Likely pathogenic ★★ same type

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-pro728ala (accessed [today's date]).

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