Is CDC42EP1 p.Arg76Cys (c.226C>T) pathogenic?

CDC42EP1 p.Arg76Cys (c.226C>T) is classified Uncertain significance in CDC42EP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-11). AlphaMissense: likely benign (0.2054); Ultra-rare (popmax 0.0118%, amr).

How common is CDC42EP1 p.Arg76Cys (c.226C>T) in the general population?

CDC42EP1 p.Arg76Cys (c.226C>T) is ultra-rare (popmax 0.0118%, amr) (gnomAD).

What do computational predictors say about CDC42EP1 p.Arg76Cys (c.226C>T)?

AlphaMissense predicts likely benign (score 0.2054) — an in-silico prediction, not a clinical call.

CDC42EP1 p.Arg76Cys

c.226C>T · rs947968701 · VCV3140917

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2054 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0118%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2054	likely benign
REVEL	0.167	moderately benign-leaning
SaProt	LLR -8.53	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 3.9	GERP -0.68, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 2,467 bp · p 0.23 · regional, not allelic
Overall
CADD	25.2	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 0.0118% Admixed American · 7/59,406 alleles

Filtering AF 0.00548% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00383%

Overall 0.000997% 16/1,605,140 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0118%	8,487
South Asian	0.00332%	30,111
Remaining individualsnot grpmax-eligible	0.00322%	31,020
African / African-American	0.00134%	74,790
European (non-Finnish)	0.000256%	391,337

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: CDC42EP1
Protein: p.Arg76Cys
Coding: c.226C>T
MANE Select: NM_152243
dbSNP: rs947968701
Type: single nucleotide variant
Location: chr22:37566575 (GRCh38)
Gene constraint: LOEUF 1.863 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.46

Full CDC42EP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDC42EP1 p.Leu344Pro Uncertain significance ★★ ⚠ same type
CDC42EP1 p.Glu184= Benign ★★ same type
CDC42EP1 p.Gly308= Benign ★★ same type
CDC42EP1 p.His67= Benign ★★ same type
CDC42EP1 p.Leu194= Benign ★★ same type
CDC42EP1 p.Thr372= Benign ★★ same type
CDC42EP1 p.Ala10Thr Uncertain significance ★ ⚠ same type
CDC42EP1 p.Ala129Ser 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/cdc42ep1-p-arg76cys (accessed [today's date]).

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