Is CDC42EP2 p.Leu34Pro (c.101T>C) pathogenic?

CDC42EP2 p.Leu34Pro (c.101T>C) is classified Uncertain significance in CDC42EP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.9822); Very rare (popmax 0.005%, amr).

How common is CDC42EP2 p.Leu34Pro (c.101T>C) in the general population?

CDC42EP2 p.Leu34Pro (c.101T>C) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about CDC42EP2 p.Leu34Pro (c.101T>C)?

AlphaMissense predicts likely pathogenic (score 0.9822) — an in-silico prediction, not a clinical call.

CDC42EP2 p.Leu34Pro

c.101T>C · VCV4223392

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9822 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9822	likely pathogenic · top 7% in CDC42EP2
REVEL	0.628	indeterminate
SaProt	LLR -12.78	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 629 bp · p 0.06 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.005% Admixed American · 3/60,030 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000274% 4/1,461,748 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,010
European (non-Finnish)	8.47e-05%	1,180,030

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: CDC42EP2
Protein: p.Leu34Pro
Coding: c.101T>C
MANE Select: NM_006779
Type: single nucleotide variant
Location: chr11:65320999 (GRCh38)
Gene constraint: LOEUF 1.364 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 62.22
Residue 34: the crib domain

Full CDC42EP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDC42EP2 p.Gly93= Benign ★★ same type
CDC42EP2 p.Ala89Thr Uncertain significance ★ ⚠ same type
CDC42EP2 p.Arg11Cys Uncertain significance ★ ⚠ same type
CDC42EP2 p.Arg132His Uncertain significance ★ ⚠ same type
CDC42EP2 p.Arg22Gln Uncertain significance ★ ⚠ same type
CDC42EP2 p.Arg38Cys Uncertain significance ★ ⚠ same type
CDC42EP2 p.Arg87Cys Uncertain significance ★ ⚠ same type
CDC42EP2 p.Arg87Pro 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/cdc42ep2-p-leu34pro (accessed [today's date]).

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