Is CPLANE2 p.Arg221Trp (c.661C>T) pathogenic?

CPLANE2 p.Arg221Trp (c.661C>T) is classified Uncertain significance in CPLANE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-28). AlphaMissense: likely benign (0.069); Ultra-rare (popmax 0.0111%, nfe).

How common is CPLANE2 p.Arg221Trp (c.661C>T) in the general population?

CPLANE2 p.Arg221Trp (c.661C>T) is ultra-rare (popmax 0.0111%, nfe) (gnomAD).

What do computational predictors say about CPLANE2 p.Arg221Trp (c.661C>T)?

AlphaMissense predicts likely benign (score 0.069) — an in-silico prediction, not a clinical call.

CPLANE2 p.Arg221Trp

c.661C>T · VCV3269185

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.069 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.069	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -7.23	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.97	phastCons 0.41
Regional constraint	o/e 0.93	unconstrained · MANE · 4,691 bp · p 0.18 · regional, not allelic
Overall
CADD	17.34	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0111% European (non-Finnish) · 131/1,179,938 alleles

Filtering AF 0.00953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00896%

Overall 0.00874% 141/1,613,176 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0111%	9,007
Admixed American	0.00667%	14,999
South Asian	0.00329%	30,357
African / African-American	0.00267%	37,521
Remaining individualsnot grpmax-eligible	0.0016%	62,490

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.Arg221Trp
Coding: c.661C>T
MANE Select: NM_030907
Type: single nucleotide variant
Location: chr1:16232164 (GRCh38)
Gene constraint: LOEUF 1.649 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.38
Residue 221: 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-arg221trp (accessed [today's date]).

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