Is CPLANE2 p.Pro166Ser (c.496C>T) pathogenic?

CPLANE2 p.Pro166Ser (c.496C>T) is classified Uncertain significance in CPLANE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely benign (0.0783); Ultra-rare (popmax 0.0154%, sas).

How common is CPLANE2 p.Pro166Ser (c.496C>T) in the general population?

CPLANE2 p.Pro166Ser (c.496C>T) is ultra-rare (popmax 0.0154%, sas) (gnomAD).

What do computational predictors say about CPLANE2 p.Pro166Ser (c.496C>T)?

AlphaMissense predicts likely benign (score 0.0783) — an in-silico prediction, not a clinical call.

CPLANE2 p.Pro166Ser

c.496C>T · VCV4006224

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0783 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0783	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -10.41	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.22 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.8	phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 4,691 bp · p 0.18 · regional, not allelic
Overall
CADD	19.42	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 0.0154% South Asian · 14/91,076 alleles

Filtering AF 0.0092% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.000991% 16/1,614,022 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0154%	6,505
East Asian	0.00223%	44,896
European (non-Finnish)	8.47e-05%	1,180,034

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: CPLANE2
Protein: p.Pro166Ser
Coding: c.496C>T
MANE Select: NM_030907
Type: single nucleotide variant
Location: chr1:16232541 (GRCh38)
Gene constraint: LOEUF 1.649 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.38
Residue 166: the 'small gtpase-like' region

Full CPLANE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CPLANE2 p.Arg106Cys Uncertain significance ★ ⚠ same type
CPLANE2 p.Arg106His Uncertain significance ★ ⚠ same type
CPLANE2 p.Arg111Cys Uncertain significance ★ ⚠ same type
CPLANE2 p.Arg148Cys Uncertain significance ★ ⚠ same type
CPLANE2 p.Arg160Cys Uncertain significance ★ ⚠ same type
CPLANE2 p.Arg160His Uncertain significance ★ ⚠ same type
CPLANE2 p.Arg188Gln Uncertain significance ★ ⚠ same type
CPLANE2 p.Arg188Trp Uncertain significance ★ ⚠ 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/cplane2-p-pro166ser (accessed [today's date]).

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